Bicyclic prostaglandins

ABSTRACT

Bicyclic prostaglandins and pharmaceutical and veterinary compositions containing them having numerous pharmaceutical or veterinary utilities including, for example, hypotensive, vasodilatory, anti-aggregating, luteolytic, and cytoprotective activities. Processes for preparing the compounds are also disclosed.

This is a divisional application of Ser. No. 859,703, filed Dec. 12,1977 now abandoned.

The present invention relates to 2-oxa-bicyclic prostaglandins, to amethod for their preparation and to pharmaceutical and veterinarycompositions containing them.

The compounds of the invention are 2-oxa-bicyclic prostaglandins offormula (I) ##STR1## wherein R is a member selected from the groupconsisting of (a) a free or esterified carboxy group; ##STR2## whereineach of the R' groups, which are the same or different, is C₁ -C₆ alkylor phenyl; (c) --CH₂ OH; ##STR3## wherein R_(a) and R_(b) areindependently selected from the group consisting of hydrogen, C₁ -C₆alkyl, C₂ -C₆ alkanoyl and phenyl; (e) a radical ##STR4## (f) --C═N; Z₁is hydrogen or halogen;

p is zero or an integer of 1 to 7;

q is 1 or 2;

R₁ is hydrogen, hydroxy, C₁ -C₆ alkoxy, ar-C₁ -C₆ -alkoxy, acyloxy;

Y is a member selected from the group consisting of --CH₂ CH₂ --,--C.tbd.C--, ##STR5## wherein Z₂ is hydrogen or halogen; one of R₂ andR₅ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or aryl,and the other is hydroxy, C₁ -C₆ alkoxy, ar-C₁ -C₆ -alkoxy or R₂ and R₅,taken together, form an oxo group;

each of R₃ and R₄, which are the same or different, may be hydrogen, C₁-C₆ alkyl or fluorine or R₃ and R₄, taken together with the carbon atomto which they are linked, form the radical ##STR6## or the radical##STR7## each of n₁ and n₂, which are the same or different, is zero oran integer of 1 to 6;

X is a member selected from the group consisting of --O--, --S-- and--(CH₂)_(m) --, wherein m is zero or 1;

R₆ is a member selected from the group consisting of

(a') hydrogen;

(b') C₁ -C₄ alkyl;

(c') a C₃ -C₉ cycloaliphatic radical, unsubstituted or substituted byone or more substituents selected from the group consisting of C₁ -C₆alkyl and C₁ -C₆ alkoxy;

(d') aryl, unsubstituted or substituted by one or more substituentsselected from the group consisting of halogen, halo-C₁ -C₆ -alkyl, C₁-C₆ alkyl and C₁ -C₆ alkoxy; and

(e') a saturated or unsaturated heterocyclic ring, unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of halogen, halo-C₁ -C₆ -alkyl, C₁ -C₆ alkyl and C₁ -C₆alkoxy.

Also the pharmaceutically or veterinarily acceptable salts as well asthe optical antipodes, i.e. the enantiomers, the racemic mixtures of theoptical antipodes, the geometric isomers and their mixtures and themixtures of the diastereoisomers of the compounds of formula (I) areincluded in the scope of the present invention.

In the formulae of this specification the broken line ("") indicatesthat a substituent bound to the cyclopentane ring is in theα-configuration, i.e. below the plane of the ring, a substituent boundto the 2-oxa-bicyclic system is in the endo-configuration and asubstituent bound to a chain is in the S-configuration; the heavy solidline ( ) indicates that a substituent bound to the cyclopentane ring isin the β-configuration, i.e. above the plane of the ring, a substituentbound to the 2-oxa-bicyclic system is in the oxo-configuration and asubstituent bound to a chain is in the R-configuration, the wavy lineattachment ( ) indicates that a substituent does not possess a definitestereochemical identity i.e. that a substituent bound to thecyclopentane ring may be both in the α- and in the β-configuration, asubstituent bound to the 2-oxo-bicyclic system may be both in theendo-or in the exo-configuration and a substituent bound to a chain maybe both in the S- and in the R-configuration.

In the compounds of the above formula (1) the heterocyclic ring B iscis-fused with the cyclopentane ring A and the two bonds indicated bythe dotted lines (••••) are both in the α-configuration with respect tothe ring A.

The side chain β-linked to the cyclopentane ring A is intrans-configuration with respect to the α-fused heterocyclic ring B andconsequently it is an exo substituent with respect to the 2-oxa-bicyclicsystem.

The carbon atom of the heterocyclic ring B bearing the side chain##STR8## bears also an hydrogen atom.

When the side chain ##STR9## is in the endo-configuration with respectto the 2-oxa-bicyclic system, then said hydrogen atom is anexo-substituent and its absolute configuration is reported as β whilewhen the chain ##STR10## is in the exo-configuration, then said hydrogenatom is an endo-substituent and its absolute configuration is reportedas α.

The compounds of the invention wherein the chain ##STR11## is theexo-configuration, the hydrogen atom linked to the same carbon atom ofthe ring B having necessarily the α-absolute configuration, are reportedas 6αH-6,9α-oxide (formula I; q=1) and 5αH-6,9α-oxide (formula I; q=2)prostanoic acid derivatives (prostaglandin numbering), while thecompounds wherein the chain ##STR12## is in the endo-configuration, thehydrogen atom linked to the same carbon atom of the ring B havingnecessarily the β-absolute configuration, are reported as 6βH-6,9α-oxide(formula I; q=1) and 5βH-5,9α-oxide (formula I; q=2) prostanoic acidderivatives (prostaglandin numbering). Alternatively the 6βH-6,9α-oxideprostanoic acid derivatives are reported as(2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-alkanoic acid derivatives, the5βH-5,9α-oxide prostanoic acid derivatives as(2'-oxa-bicyclo[4.3.0]nonan-3'-exo-yl)-alkanoic acid derivatives, the6βH-6,9α-oxide prostanoic acid derivatives as(2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-alkanoic acid derivatives andthe 5βH-5,9α-oxide prostanoic acid derivative as(2'-oxa-bicyclo[4.3.0]nonan-3'-endo-yl)-alkanoic acid derivatives. The6αH-6,9α-oxide and 5αH-5,9α-oxide prostanoic acid derivatives have ahigher chromatographic mobility (i.e. a higher R_(f)) and a lesspositive rotatory power ([α]_(D)) than the corresponding 6βH-6,9α-oxideand 5βH-5,9α-oxide derivatives.

All the above notations refer to the natural compounds; thed,1-compounds are mixtures containing equimolar amounts of nat-compoundswhich possess the above reported absolute stereochemistry and ofent-compounds which are mirror-like images of the formers; in theent-compounds the stereochemical configuration is the opposite at allthe asymmetric centers with respect to the configuration of the naturalcompounds and the prefix ent indicates just this.

The alkyl, alkenyl, alkynyl, alkoxy, and alkanoyloxy groups are branchedor straight chain groups.

Preferably R is a free, salified or esterified carboxy group.

An ar-C₁ -C₆ -alkoxy group is preferably benzyloxy.

An aryl group is preferably phenyl,α-naphthyl or β-naphthyl.

A halo-C₁ -C₆ -alkyl group is preferably trihalo-C₁ -C₆ -alkyl, inparticular trifluoromethyl.

A C₁ -C₆ alkyl group is preferably methyl, ethyl or propyl.

A C₁ -C₆ alkoxy group is preferably methoxy, ethoxy or propoxy.

A C₂ -C₆ alkenyl radical is preferably vinyl.

A C₂ -C₆ alkynyl radical is preferably ethynyl.

When R is an esterified carboxy group it is preferably a --COOR_(c)group wherein R_(c) is a C₁ -C₁₂ alkyl radical, in particular methyl,ethyl, propyl and heptyl, or a C₂ -C₁₂ alkenyl radical, in particularallyl.

Preferably Z₁ is hydrogen.

When Z₁ is halogen, it is preferably chlorine or bromine.

p is preferably an integer of 1 to 3.

When R₁ is acyloxy, it is preferably C₂ -C₁₂ alkanoyloxy (in particularC₂ -C₆ alkanoyloxy, e.g., acetoxy, propionyloxy) or benzoyloxy.

When Z₂ is hydrogen, it is preferably chlorine, bromine or iodine.

Preferably R₃ and R₄ are independently selected from the groupconsisting of hydrogen, C₁ -C₆ alkyl and fluorine.

n₁ is preferably zero or an integer of 1 to 3; n₂ is preferably aninteger of 1 to 3.

When R₆ is a C₃ -C₉ cycloaliphatic radical, it is preferably a C₃ -C₉cycloalkyl radical e.g. cyclopentyl, cyclohexyl and cycloheptyl or a C₃-C₉ cycloalkenyl radical, e.g. cyclopentyl, cyclohexyl andcycloheptenyl.

When R₆ is a heterocyclic ring, it may be either a heteromonocyclic ringor a heterobicyclic ring and contains at least one heteroatom selectedfrom the group consisting of N, S and O.

Examples of preferred heteromonocyclic radicals are tetrahydrofuryl,tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl.

Examples of preferred heterobicyclic radicals are2-oxa-bicyclo[3.3.0]octyl, 2-oxa-bicyclo[3.4.0]nenyl,2-thia-bicyclo[3.3.0]octyl, and 2-thia-bicyclo[3.4.0]nonyl and theiraromatic analogs.

Pharmaceutically or veterinarily acceptable salts of the compounds offormula (I) are e.g. those with pharmaceutically and veterinarilyacceptable bases. Pharmaceutically and veterinarily acceptable bases areeither inorganic bases such as, for example, alkaline hydroxides andalkaline-earth hydroxides as well as aluminium and zinc hydroxides ororganic bases e.g. organic amines such as, for example, methylamine,dimethylamine, trimethylamine, ethylamine, dibutylamine,N-methyl-N-hexylamine, decylamine, dodecylamine, allylamine,cyclopentylamine, cyclohexylamine, benzylamine, dibenzylamine,α-phenyl-ethylamine, β-phenyl-ethylamine, ethylenediamine,diethylenetriamine, morpholine, piperidine, pyrrolidine, piperazine, aswell as the alkyl derivatives of the latter four bases, mono-, di- andtri-ethanolamine, ethyl-diethanolamine, N-methyl-ethanolamine,2-amino-1-butanol, 2-amino-2-methyl-1-propanol, N-phenyl-ethanolamine,galactamine, N-methyl-glucamine, N-methylglucosamine, ephedrine,procaine, dehydroabietilamine, lysine, arginine and other α or β amineacids. Preferred salts of the invention are those of the compounds offormula (I) wherein R is --COOR_(d) wherein R_(d) is a pharmaceuticallyor veterinarily acceptable cation deriving from one of the abovementioned bases.

Particularly preferred compounds of the invention are 6βH-6,9α-oxide and5βH-5,9α-oxide compounds of formula (I) wherein R is a free carboxygroup and R₆ is C₁ -C₄ alkyl, C₅ -C₇ cycloalkyl or optionallysubstituted phenyl. The prefixes nor, dinor, trinor, tetranor- etc., areused to identify the compounds of formula (I) wherein the side chainbound to the cyclopentane ring A is one, two, three, four, etc. carbonatoms shorter than the analogous chain in the natural prostaglandins.

Specific examples of preferred compounds of the invention are thefollowing:

13t-6β-6,9α-oxide-11α, 15S-dihydroxy-prost-13-enoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-prost-13-ynoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-prostanoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-15-methyl-prost-13-enoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-15-methyl-prost-13-ynoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-15-methyl-prostanoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-15,20-dimethyl-prost-13-enoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-15,20-dimethyl-prost-13-ynoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-15,20-dimethyl-prostanoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-20-methyl-prost-13-enoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-20-methyl-prost-13-ynoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-20-methyl-prostanoic acid;

13t-6βH-6,9α-oxide-15S-hydroxy-prost-13-enoic acid;

6βH-6,9α-oxide-15S-hydroxy-prost-13-ynoic acid;

6βH-6,9α-oxide-15S-hydroxy-prostanoic acid;

13t-6βH-6,9α-oxide-15S-hydroxy-15-methyl-prost-13-enoic acid;

6βH-6,9α-oxide-15S-hydroxy-15-methyl-prost-13-ynoic acid;

6βH-6,9α-oxide-15S-hydroxy-15-methyl-prostanoic acid;

13t-6βH-6,9α-oxide-15S-hydroxy-15,20-dimethyl-prost-13-enoic acid;

6βH-6,9α-oxide-15S-hydroxy-15,20-dimethyl-prost-13-ynoic acid;

6βH-6,9α-oxide-15S-hydroxy-15,20-dimethyl-prostanoic acid;

13t-6βH-6,9α-oxide-15S-hydroxy-20-methyl-prost-13-enoic acid;

6βH-6,9α-oxide-15S-hydroxy-20-methyl-prost-13-ynoic acid;

6βH-6,9α-oxide-15S-hydroxy-20-methyl-prostanoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-14-bromo-prost-13-enoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-14-chloro-prost-13-enoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-14-bromo-15-methyl-prost-13-enoicacid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-14-bromo-20-methyl-prost-13-enoicacid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-14-bromo-15,20-dimethyl-prost-13-enoicacid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-16,16-dimethyl-prost-13-enoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-16-methyl-16-butoxy-20,19,18-trinor-prost-13-enoicacid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-20,19,18-trinor-prost-13-enoicacid and the single 16(S)-and 16(R)-fluoro isomer;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-prost-13-enoicacid;

6βH-6,9α-oxide-11α,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-prost-13-ynoicacid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-16-phenoxy-20,19,18,17-tetranor-13-enoicacid and the p-fluoro, p-chloro, p-methoxy, o-fluoro, m-fluoro,m-trifluoromethyl, m-chloro-phenoxy analogs thereof;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-17-(2'-tetrahydrofuryl)-20,19,18-trinor-prost-13-enoicacid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-17-(2'-tetrahydrothienyl)-20,19,18-trinor-prost-13-enoicacid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-20-ethyl-prost-13-enoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-16-benzyloxy-20,19,18,17-tetranor-13-enoicacid and the p-fluoro, p-chloro, p-methoxy, o-fluoro, m-fluoro,m-trifluoromethyl, m-chloro-benzyloxy analogs thereof;

13t-5βH-5,9α-oxide-11α,15S-dihydroxy-prost-13-enoic acid;

5βH-5,9α-oxide-11α, 15S-dihydroxy-prostanoic acid;

5βH-5,9α-oxide-11α,15S-dihydroxy-prost-13-ynoic acid;

13t-5βH-5,9α-oxide-11α,15S-dihydroxy-16S-methyl-prost-13-enoic acid;

13t-5βH-5,9α-oxide-11α,15S-dihydroxy-16R-methyl-prost-13-enoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-16S-methyl-prost-13-enoic acid;

13t-6βH-6,9α-oxide-11α,15S-dihydroxy-16R-methyl-prost-13-enoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-16S-methyl-prost-13-ynoic acid;

6βH-6,9α-oxide-11α,15S-dihydroxy-16R-methyl-prost-13-ynoic acid,

as well as the 5-bromo, and 5-iodo, the 5-chloro analogs of all the6βH-6,9α-oxide derivatives above listed, as well as the 4-bromo, the4-iodo, the 4-chloro analogs of all the 5βH-5,9α-oxide derivatives abovelisted, as well as the 15R-epimers, the 15-oxo-derivatives and the 6αH-and the 5αH-diastereoisomers of all the compounds mentioned above.

The compounds of the invention are prepared by a process comprising:

(a) halocyclizing a compound of formula (II) ##STR13## wherein p, q, Y,n₁, n₂, R₃, R₄, X and R₆ are as defined above, D is cis- or trans--CH═CH--, R" is (a") a free or esterified carboxy group; (b") a group##STR14## wherein each of the R' groups is as defined above; (c") thegroup --CH₂ --R₇, wherein R₇ is hydroxy or a known protecting groupbound to the --CH₂ --group by an ethereal oxygen atom; (d") ##STR15##wherein R_(a) and R_(b) are as defined above; (e") a radical of formula##STR16## R'₁ is hydrogen, hydroxy, C₁ -C₆ alkoxy, ar-C₁ -C₆ -alkoxy,acyloxy or a known protecting group bound to the ring by an etherealoxygen atom; one of R'₂ and R'₅ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl or aryl and the other is hydroxy, C₁ -C₆ alkoxy,ar-C₁ -C₆ -alkoxy or a known protecting group bound to the chain by anethereal oxygen atom, or R'₂ and R'₅ taken together, form an oxo group,so obtaining, after the removal of the known protecting groups, ifpresent, a compound of formula (I) wherein Z₁ is halogen and, ifnecessary, deetherifying and/or, if desired, dehalogenerating theobtained compound to give a compound of formula (I) wherein Z₁ ishydrogen; or

(b) reducing a compound of formula (III) ##STR17## wherein Q is halogenor a group Hg.sup.(+) Z.sup.(-), wherein Z.sup.(-) is OH.sup.(-) on theanionic residue of an acid, R, p, q, R₁, Y, R₂, R₅, R₃, R₄, n₁, n₂, Xand R₆ are as defined above, so obtaining a compound of formula (I)wherein Z₁ is hydrogen; or

(c) reacting a compound of formula (IV) ##STR18## wherein R", p, Z₁, q,and R₁ ' are as defined above, with a compund of formula (V) ##STR19##wherein E is a group ##STR20## wherein each of the R_(e) groups, whichare the same or different, is alkyl or aryl and Z₂, R₃, R₄, n₁, n₂, Xand R₆ are as defined above, so obtaining, after the removal of theknown protecting groups, if present, a compound of formula (I) whereinR₂ and R₅, taken together, form an oxo group and Y is --CH═CZ₂ --wherein Z₂ is as defined above and, if desired, reducing a compund offormula (I) wherein R₂ and R₅, taken together, form an oxo group and Yis --CH═CZ₂ -- wherein Z₂ is as defined above, to give a compound offormula (I) wherein one of R₂ and R₅ is hydrogen and the other ishydroxy and Y is --CH═CZ₂ --, wherein Z₂ is as defined above, or, ifdesired, converting a compound of formula (I) wherein R₂ and R₅, takentogether, form an oxo group and Y is --CH═CZ₂ -- wherein Z₂ is asdefined above, into a compound of formula (I) wherein one of R₂ and R₅is hydroxy and the other is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynylor aryl and, if desired, etherifying a compound of formula (I) whereinone of R₂ and R₅ is hydroxy and the other is hydrogen, C₁ -C₆ alkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl or aryl and Y is --CH═CZ₂ -- wherein Z₂ isas defined above, to give a compund of formula (I) wherein one of R₂ andR₅ is C₁ -C₆ alkoxy or ar-C₁ -C₆ -alkoxy and the other is hydrogen, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or aryl and Y is --CH═CZ₂ --wherein Z₂ is as defined above, and/or, if desired, hydrogenating acompound of formula (I) wherein Y is --CH═CZ₂ -- wherein Z₂ is hydrogen,to give a compound of formula (I) wherein Y is --CH₂ CH₂ -- or, ifdesired, dehydrohalogenating a compound of formula (I) wherein Z₁ ishydrogen and Y is --CH═CZ₂ -- wherein Z₂ is halogen, to give a compoundof formula (I) wherein Y is --C.tbd.C-- and Z₁ is hydrogen or, ifdesired, hydrogenating a compound of formula (I) wherein R₂ and R₅,taken together, form an oxo group and Y is --CH═CZ₂ -- wherein Z₂ ishydrogen, to give a compound of formula (I) wherein R₂ and R₅, takentogether, form an oxo group and Y is --CH₂ CH₂ -- or, if desired,dehydrohalogenating a compound of formula (I) wherein Z₁ is hydrogen, R₂and R₅, taken together, form an oxo group, and Y is --CH═CZ₂ -- whereinZ₂ is halogen, to give a compound of formula (I) wherein Z₁ is hydrogen,R₂ and R₅, taken together, form an oxo group and Y is --C.tbd.C-- and,if desired, reducing a compound of formula (I) wherein R₂ and R₅, takentogether, form an oxo group, to give a compund of formula (I) whereinone of R₂ and R₅ is hydrogen and the other is hydroxy, or, if desired,converting a compound of formula (I) wherein R₂ and R₅, taken together,form an oxo group, into a compound of formula (I) wherein one of R₂ andR₅ is hydroxy and the other is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl or aryl and, if desired, etherifying a compound of formula (I)wherein one of R₂ and R₅ is hydroxy and the other is hydrogen, C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or aryl, to give a compound offormula (I) wherein one of R₂ and R₅ is C₁ -C₆ alkoxy or ar-C₁ -C₆-alkoxy and the other is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl or aryl; and/or, if desired, converting a compound of formula(I) into another compound of formula (I) and/or, if desired, salifying acompound of formula (I) and/or, if desired, obtaining a free compound offormula (I) from a salt thereof and/or, if desired, separating a mixtureof isomers into the single isomers. In the optional steps of the aboveprocesses when only one of a few substituents are specifically mentionedfor a compound, it is understood that the other substituents have allthe meanings previously indicated for formula (I). The known protectinggroups, i.e., ether groups, are convertible to hydroxy groups under mildreaction conditions, e.g., acid hydrolysis. Examples are acetal ethers,enol ethers and silyl ethers. The preferred groups are ##STR21## whereinW is --O-- or --CH₂ -- and Alk is a lower alkyl group. When in thecompound of formula (III) Q represents a group Hg.sup.(+) Z.sup.(-),wherein Z.sup.(-) is the anionic residue of an acid, Z.sup.(-) ispreferably selected from the group consisting of Cl.sup.(-), Br.sup.(-),I.sup.(-), R₈ --COO.sup.(-), wherein R₈ is an optionallyhalo-substituted C₁ -C₁₂ alkyl group (preferably C₁ -C₆ alkyl ortrifluoromethyl) and ##STR22## wherein R₉ is, e.g., hydrogen, C₁ -C₆alkyl, halogen, e.g., bromine, or trifluoromethyl. Preferably Z.sup.(-)is Cl.sup.(-), Br.sup.(-), CH₃ COO.sup.(-), CF₃ COO.sup.(-) or ##STR23##. The halocylization of a compound of formula (II) may be performed byreaction with either a stoichiometric amount or a small excess of ahalogenating agent in an inert solvent, in either the presence or inabsence of a base.

Preferred halogenating agents are, e.g., iodine, bromine, chlorine,bromodioxane, bromopyridine, Br₂.pyridine.HBr, KI₃,pyrrolidone-hydrotribromide, an N-haloamide such asN-chloro-succinimide, N-bromo-succinimide, N-iodo-succinimide, a cuprichalide such as CuCl₂ or CuBr₂, a mixed halide such as ICl or IBr, aswell as a mixture of an alkaline chloride with an alkaline chlorate, amixture of an alkaline bromide with an alkaline bromate or a mixture ofan alkaline iodide with an alkaline bromate. Suitable solvents are, forexample, halogenated hydrocarbons such as CHCl₃, CCl₄, CH₂ Cl₂ ;aliphatic hydrocarbons such as n-hexane, n-heptane; cycloaliphatichydrocarbons such as cyclohexane, aromatic hydrocarbons such as benzene,toluene, pyridine, cyclic or linear either, e.g., dioxane,tetrahydrofuran, diehylether, dimethoxyethane; as well as mixturesthereof.

Preferred solvents are halogenated hydrocarbons, e.g. CH₂ Cl₂, sinceboth the compound of formula (II) and the halogenating agent are usuallysoluble in these solvents.

A stoichiometric amount of a base is necessary when a hydrohalic acid isformed during the halocyclization reaction. Such a base may be aninorganic base, e.g., an alkaline or an alkaline-earth oxide, carbonateor bicarbonate, e.g., CaO, CaCO₃ and K₂ CO₃, NaHCO₃, Na₂ CO₃ ; anorganic base such as a tertiary amine, e.g., triethylamine; or anaromatic base, e.g., pyridine or an alkyl-substituted pyridine; or ananionic ion-exchange resin.

The halocyclization reaction is preferably carried out at temperaturesranging from about -70° C. to about 100° C.; preferably the reaction isperformed at room temperature.

The reaction times range from few minutes to several days, but usuallydo not exceed two hours and often a few minutes are sufficient tocomplete the reaction.

When other unsaturated bonds are present in the compound of formula (II)besides the double bond contained in the substituent D, thoseunsaturated bonds may add halogen during the halocyclization reaction.The added halogen may be easily removed to reobtain the originalunsaturations, by treating the reaction product with an alkaline oralkaline-earth iodide in a suitable solvent such as, e.g., acetone attemperatures ranging from room temperature to reflux temperature butpreferably at room temperature. Reaction time may range from about 2-3hours to about 2-3 days.

The removal of the known protecting groups bound to the ring or to thechain by an ethereal oxygen atom is, whenever required, performed underconditions of mild acid hydrolysis, for example with a mono- orpoly-carboxylic acid such as formic, acetic, oxalic, citric and tartaricacid, and in a solvent, which may be water, acetone, tetrahydrofuran,dimethoxyethane or a lower aliphatic alcohol, or with a sulphonic acid,e.g., p-toluenesulphonic acid in a solvent such as a lower aliphaticalcohol, dry methanol or dry ethanol, for example, or with apolystyrene-sulphonic resin.

For example, 0.1 to 0.25 N poly-carboxylic acid (e.g., oxalic or citricacid) is used in the presence of a convenient low-boiling co-solventwhich is misible with water and which can be easily removed in vacuo atthe end of the reaction.

All the cyclization, reactions described in this specification such ase.g. the hereabove described halocyclization of a compound of formula(II) to give a compound of formula (I) wherein Z₁ is halogen, theherebelow described cyclization of a compound of formula (II) to give acompound of formula (III) wherein Q is Hg.sup.(+) Z.sup.(-) and theherebelow described cyclization of a compound of formula (VI) areidentical reactions as to their mechanism and the number of the isomerscontained in the reaction mixture in the same for all the abovecyclizations. Thus for example the above halocyclization reaction of acompound of formula (II) can give to a mixture of four components, i.e.compounds of formula (I) wherein Z₁ is halogen, consisting in a coupleof diastereoisomers having the side chain ##STR24## in theexo-configuration and differing each other for the S or R configurationof the halogen Z₁ and a couple of diastereoismers having the side chain##STR25## in the endoconfiguration and differing each other for the S orR configuration of the halogen Z₁.

While the chromatographic mobility (R_(f)) of the endo-isomer is clearlydifferent from the chromatographic mobility of the exoisomer, thedifference of R_(f) between two endo- (or exo-) isomers differing eachother only for the S or R configuration of the Z₁ substituent, is verysmall.

The couple of diastereoisomers wherein the chain ##STR26## is in theexo-configuration may be separated from the couple of diastereoisomerswherein said chain is in the endo-configuration by fractionalcrystallization e.g. from diethylether but preferably by tin layerpreparative chromatography, by column chromatography or by high speedliquid chromatography.

The separation by tin layer preparative chromatography or by columnchromatography is preferably carried out on a support of silica gel ormagnesium silicate with methylene chloride, diethylether,isopropylether, ethylacetate, benzene, methyl acetate, cyclohexane ortheir mixtures as elution solvents.

The reductive dehalogenation of a compound of formula (I) wherein Z₁ ishalogen, to give a compound of formula (I) wherein Z₁ is hydrogen, isperformed by reduction, e.g., wih chromous acetate or a hydride such astri(n-butyl)tin hydride, or by catalytic hydrogenation. When it isdesired to obtain a compound of formula (I) wherein Y is --C.tbd.C-- or--CH═CZ₂ -- wherein Z₂ is as defined above, the dehalogenation iscarried out only by reduction, e.g., with tri(n-butyl)tin hydride orchromous acetate.

When it is desired to obtain a compound of formula (I) wherein R₂ and R₅taken together form an oxo group, by the dehalogenation of the compoundof formula (I) wherein Z₁ is halogen, the reaction time should notexceed half an hour.

When the reductive dehalogenation is carried out with chromous acetate,this reagent is added, with stirring, to a cooled solution of thecompound of formula (I) wherein Z, is halogen, in a mixture of ethanoland aqueous sodium or potassium hydroxide under an atmosphere ofnitrogen. The reaction mixture is then stirred one to three days at roomtemperature, according to the method described in J. Am. Chem. Soc. 76,5499 (1954).

When the dehalogenation is carried out with tri(n-butyl)tin hydride,about 1.2 equivalents of the reducing agent are used for each equivalentof the compound of formula (I) wherein Z₁ is halogen. Suitable solventsfor the reaction are aromatic hydrocarbons such as benzene or tolueneand the temperatures preferably are between room temperature and about70° C.

Preferably the reaction is carried out at about 55° C. in benzene andlasts about 12 hours.

The catalytic hydrogenation of a compound of formula (I) wherein Z₁ ishalogen to give a compound of formula (I) wherein Z₁ is hydrogen and Yis --CH₂ CH₂ -- may be performed either at room temperature or byheating this compound, e.g., at 30°-60° C. at atmospheric pressure orunder pressure, e.g., at 1.1-2 atm, in a solvent such as, e.g., a loweraliphatic alcohol, tetrahydrofuran, dioxane, benzene, toluene in thepresence of a catalyst such as palladium or platinum or charcoal orCaCO₃ and optionally in the presence of an ammonium salt, e.g., ammoniumacetate or proprionate.

The reductive dehalogenation converts a compound of formula (I) whereinZ₁ is halogen into a compound of formula (I) wherein Z₁ is hydrogen andtherefore during the dehalogenation the carbon atom carrying the Z₁substituent loses its asymmetry.

The number of the possible diastereoisomers consequently contained inthe dehalogenation reaction mixture is lower than the number ofdiastereoisomers contained in the halocyclization reaction mixture. Whenthe reductive dehalogenation is carried out directly on the mixture offour diastereoisomers obtained from the halocyclization process, amixture of two only diastereoisomers of formula (I) wherein Z₁ ishydrogen is obtained, differing each other for the exo- or endo-configuration of the side chain CH₂ --(CH₂)_(p) --R.

When the reductive dehalogenation is carried out on a single couple ofdiastereoisomers of formula (I) having the side chain ##STR27## whereinZ₁ is halogen, in the exo- or in the endo-configuration and differingeach other for the S or R configuration of Z₁, then only one isomer offormula (I) wherein Z₁ is hydrogen is obtained wherein the side chainCH₂ --(CH₂)_(p) --R is in the exo- or in the endo-configuration.

If a mixture of the above diastereoisomers is obtained the singlediastereoisomers may be easily separated by fractional crystallizationor by column chromatography as described above for the separation of thediastereoisomers wherein Z₁ is halogen.

The reduction of the compound of formula (III) may be carried out bytreatment with mixed hydrides such as alkaline, e.g., sodium, potassiumor lithium, borohydrides, with alkaline-earth, e.g., calcium ormagnesium, borohydrides in an inert solvent, preferably a solventmiscible with water, such as tetrahydrofuran, dimethoxyethane or loweraliphatic alcohols, e.g. methanol or ethanol; or with tri(n-butyl)tinhydride in benzene or toluene, preferably benzene; or also by treatmentwith hydrazine hydrate in a lower aliphatic alcohol, e.g., methanol orethanol as solvent, at temperatures varying from room temperature to thereflux temperature of the solvent used.

When it is desired to obtain compounds of formula (I) wherein Z₁ ishydrogen and R₂ and R₅ taken together form an oxo group, the reductionof the compound of formula (III) is preferably carried out withtri(n-butyl)tin hydride for a short reaction time, preferably a timevarying from about 5 minutes to about half an hour.

During the above reduction of a compound of formula (III) the carbonatom carrying the Q substituent loses its asymmetry and therefore thenumber of the possible diastereoisomers contained in the reactionmixture at the end of the reduction process is half the number of thdiastereoisomers contained in the starting material, analogously to whatabove reported with regards to dehalogenation of a compound of formula(I) wherein Z₁ is halogen.

When in the compound of formula (V) E is ##STR28## wherein R_(e) isaryl, it is preferably phenyl; when R_(e) is alkyl, it is preferably C₁-C₆ alkyl. The reaction between an aldehyde of formula (IV) and acompound of formula (V) is carried out with an excess of the compound offormula (V), e.g., at least 1.01 molar equivalent of the compound offormula (V) for each mole of the compound of formula (IV).

Any inert solvent can be used, such as linear and cyclic ethers, e.g.ethyl ether, tetrahydrofuran, dioxane, dimehoxyethane, aliphatic oraromatic hydrocarbons, e.g., n-heptane, n-hexane, benzene, toluene orhalogenated hydrocarbons, e.g. methylenechloride, tetrachloroethane andalso mixtures of these solvents. The reaction temperature may varybetween the freezing and the boiling points of the solvent.

When the reaction is carried out with a compound of formula (V) whereinE is ##STR29## the preferred temperature is the room temperature i.e.from about 10° C. to about 25° C., when the reaction is carried out witha compound of formula (V) wherein E is (C₆ H₅)₃ P.sup.(+) --, thepreferred temperature is the reflux temperature of the solvent.

The product of the reaction between a compound of formula (IV) and acompound of formula (V) is a mixture of a compound of formula (I)wherein Y is trans--CH═CZ₂ -- wherein Z₂ is as defined above and acompound of formula (I) wherein Y is cis--CH═CZ₂ -- wherein Z₂ is asdefined above, in a ratio varying between approximately 90:10 and 95:5.

The compound of formula (I) wherein Y is trans--CH═CZ₂ -- wherein Z₂ isas defined above, may be separated from the mixture by crystallizationwith a suitable solvent, while the compound of formula (I) wherein Y iscis--CH═CZ₂ -- wherein Z₂ is as defined above, may be obtained byconcentration of the mother liquor and subsequent chromatographicseparation of the residue, either by column or preparative TLCchromatography using silica gel or magnesium silicate as support ande.g. methylene chloride, diethylether, isopropylether, ethylacetate,benzene, cyclohexane or their mixtures as elution solvents.

The removal of the protecting groups, if present, may be performed bymild acid hydrolysis as described above for the compounds obtained bythe halocyclization and the reduction processes.

Either the optional reduction of a compound of formula (I) wherein R₂and R₅, taken together form an oxo group, and Y is --CH═CZ₂ --, whereinZ₂ is as defined above, to give a compound of formula (I) wherein Y is--CH═CZ₂ --, wherein Z₂ is as defind above and wherein one of R₂ and R₅is hydrogen and the other is hydroxy or the optional conversion of acompound of formula (I) wherein R₂ and R₅, taken together form an oxogroup and Y is --CH═CZ₂ -- wherein Z₂ is as defined above, into acompound of formula (I) wherein Y is --CH═CZ₂ --, wherein Z₂ is asdefined above, and wherein one of R₂ and R₅ is hydroxy and the other isC₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or aryl must be regarded asdifferent applications of one only reaction which is a 1.2 polaraddition to the carbonyl group. The optional reduction of an obtainedcompound of formula (I) wherein R₂ and R₅ taken together form an oxogroup, and Y is --CH═CZ₂ --, wherein Z₂ is as defined above, to give acompound of formula (I) wherein Y is --CH═CZ₂ --, wherein Z₂ is asdefined above, and wherein one of R₂ and R₅ is hydrogen and the other ishydroxy, is preferably carried out with alkaline or alkaline-earth metalborohydrides, preferably sodium, lithium, calcium, magnesium or zincborohydride, using from 0.5 to 6 moles of the reducing agent for eachmole of the compound of formula (I). The reduction may be performedeither in aqueous or anhydrous inert solvents such as linear or cyclicethers, e.g., ethyl ether, tetrahydrofurna, dimethoxyehtane, dioxane oraliphatic or aromatic hydrocarbons, e.g., n-heptane or benzene, orhalogenated hydrocarbons, e.g. methylene dichloride, or hydroxylatedsolvents, e.g., ethyl, methyl or isopropyl alcohol, or mixtures of thesesolvents. The reaction temperature may vary between approximately -40°C. and the boiling point of the solvent used, but the preferredtemperature ranges from about -20° C. to about 25° C.

This reduction leads to a mixture of the two epimeric ##STR30## alcoholsfrom which the single epimers can be separated, if desired, byfractional crystallization, e.g., with diethylether, n-hexane,n-heptane, cyclohexane but preferably by chromatography either on silicagel or magnesium silicate columns or preparative TLC chromatographywith, for example, silica gel, eluting, e.g., with CH₂ Cl₂, ethyl ether,isopropyl ether, ethyl acetate, methyl acetate, benzene, cyclohexane ormixtures of these, or by high speed liquid chromatography.

The optional convention of a compound of formula (I) wherein R₂ and R₅taken together form an oxo group and Y is --CH═CZ₂ --, wherein Z₂ is asdefined above, into a compound of formula (I) wherein one of R₂ and R₅is hydroxy and the other is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynylor aryl and Y is --CH═CZ₂ -- wherein Z₂ is as defined above, may becarried out by treatment with a Grignard reagent of formula R'''-MgHal,wherein Hal is halogen, preferably bromine or iodine and R''' is C₁ -C₆alkyl, C₂ -C₆ alkynyl, C₂ -C₆ alkenyl or aryl, preferably methyl, vinyl,ethynyl, phenyl. The Grignard reaction is carried out with 1.05 to 2moles of the magnesium derivative for each mole of ketone, operating inanhydrous solvents which may be linear or cyclic ethers, e.g., ethylether, etrahydrofuran, dioxiane, dimethoxyethane or aliphatic oraromatic hydrocarbons, e.g., n-heptane, n-hexane, benzene, toluene, attemperatures varying from approximately -70° C. to the boiling point ofthe solvent used. The preferred temperature range between -60° C. and10° C.

The optional etherification of a compound of formula (I) wherein Y is--CH═CZ₂ --, wherein Z₂ is as defined above, and one of R₂ and R₅ ishydroxy and the other is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl or aryl to give a compound of formula (I) wherein Y is --CH═CZ₂--, wherein Z₂ is as defined above, and one of R₂ and R₅ is C₁ -C₆alkoxy or aralkoxy and the other is hydrogen, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl or aryl, may be carried out, for example, byreaction with an optionally aryl-substituted diazoalkano in the presenceof a catalyst such as fluoboric acid or borontrifluoride and in anorganic solvent such as dichloromethane or by reaction of the free orsalified hydroxy group with an alkyl or aralkyl halide in presence of abase such as silver oxide and in a solvent such as dimethylsulphoxide ordimethylformamide.

The optional hydrogenation of a compound of formula (I) wherein Y is--CH═CZ₂ --, wherein Z₂ is hydrogen, to give a compound of formula (I)wherein Y is --CH₂ --CH₂ -- is carried out e.g., catalytically,preferably in an alcoholic solvent, in the presence of platinum orpalladium on charcoal as catalyst at temperatures varying from about-40° C. to the reflux temperature of the solvent. When it is desired toobtain compounds of formula (I) wherein Z₁ is halogen and Y is --CH₂--CH₂ -- hydrogenation is preferably carried out at temperatures rangingfrom about -40° C. to about -20° C.

The optional dehydrohalogenation of a compound of formula (I) wherein Z₁is hydrogen, and Y is --CH═CZ₂ --, wherein Z₂ is halogen, so as toobtain the corresponding compounds of formula (I) wherein Z₁ is hydrogenand Y is --C.tbd.C--, may be carried out using a dehydrohalogenatingagent preferably selected from the group consisting of adimethylsulfinylcarbanion of formula CH₃ SCCH₂.sup.(-),diazabicycloundecene, diazabicyclononene, the amide or the alkoxide ofan alkaline metal. From 1 to 5, and preferably from 1.5 to 1.8, molarequivalents of the basic dehydrohalogenating agent may be employed foreach mole of the compound of formula (I) wherein Y is --CH═CZ₂ --,wherein Z₂ is halogen.

This dehydrohalogenation process is preferably carried out in theabsence of atmospheric oxygen, in an inert solvent such asdimethylsulphoxide, dimethylformamide, hexamethylphosphoramide: a linearor cyclic ether, e.g., dimethoxyethane, tetrahydrofuran, dioxane; anaromatic hydrocarbon, e.g., benzene, toluene; or liquid ammonia or amixture of these solvents. The reaction temperature may vary between theliquefaction point of the ammonia and approximately 100° C., but thepreferred temperature is room temperature.

Depending on the solvent, the reaction temperature and the molar ratioused between the reagent and the compound, the reaction time may varyfrom a few minutes to several hours.

The optional reduction of a compound of formula (I) wherein R₂ and R₅taken together form an oxo group and Y is --CH₂ --CH₂ -- or --C.tbd.C--to give a compound of formula (I) wherein one of R₂ and R₃ is hydrogenand the other is hydroxy and Y is --CH₂ --CH₂ -- or --C.tbd.C-- may becarried out as described above for the analogous reduction of a compoundof formula (I) wherein R₂ and R₅ taken together form an oxo group and Yis --CH═CZ₂ --, wherein Z₂ is as defined above. The optional conversionof a compound of formula (I) wherein R₂ and R₅ taken together form anoxo group and Y is --CH₂ --CH₂ or --C.tbd.C-- into a compound of formula(I) wherein one of R₂ and R₅ is hydroxy and the other is C₁ -C₆ alkyl,C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or aryl may be effected under the samereaction conditions described above for the analogous conversion of thecompounds of formula (I) wherein Y is --CH═CZ₂ --, wherein Z₂ is asdefined above.

Also the optional etherification of a compound of formula (I) whereinone of R₂ and R₅ is hydroxy and the other is hydrogen or C₁ -C₆ alkyl,C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or aryl and Y is --CH₂ --CH₂ -- or--C.tbd.C-- may be carried out as described above for the etherificationof a compound of formula (I) wherein one of R₂ and R₅ is hydrogen andthe other is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₁ -C₆ alkynyl oraryl and Y is --CH═CZ₂ --, wherein Z₂ is as defined above.

The optional conversion of a compound of formula (I) into anothercompound of formula (I) as well as the salification of a compound offormula (I), the preparation of a free compound from a salt and theseparation of the isomers from a mixture may be carried out by knownmethods.

Thus, for example, a compound of formula (I) wherein one of R₂ and R₅ ishydrogen and the other is hydroxy may be converted into a compound offormula (I) wherein R₂ and R₅ taken together form an oxo group byoxidation. The oxidation may be carried out by treatment with an excessof activated manganese dioxide in an inert solvent preferably ahalogenated inert solvent such as dichloromethane or chloroform at roomtemperature for a reaction time varying between several hours and one ormore days.

Alternatively, the oxidation may be carried out by reaction with a1.1-1.2 molar equivalent of dichlorodicyanobenzoquinone (DDQ) in aninert solvent such as dioxane, tetrahydrofuran, benzene or a mixture ofthese at temperatures ranging from about 40° C. to the boiling point ofthe solvent. A compound of formula (I) wherein R is a free carboxy groupmay be converted into a compound of formula (I) wherein R is anesterified carboxy group, e.g., a C₁ -C₁₂ carbalkoxy group, by knownmethods, e.g., by reaction with the appropriate alcohol, e.g., a C₁ -C₁₂aliphatic alcohol, in the presence of an acid catalyst, e.g.,p-toluensulphonic acid and also by treatment with a diazoalkane. Theoptional conversion of a compound of formula (I) wherein R₁ is hydroxyinto a compound of formula (I) wherein R₁ is acyloxy, if desired, may beperformed in a conventional manner, e.g., by treatment with an anhydricor a halide, such as a chloride of the appropriate carboxylic acid inthe presence of a base. When one of R₂ and R₅ is hydroxy, this hydroxygroup may be protected before the acylation by one of the knownprotecting group mentioned above.

The optional conversion of a compound of formula (I) wherein R is anesterified carboxy group into a compound of formula (I) wherein R is afree carboxy group, if desired, may be carried out by the usual methodsof saponification, e.g., by treatment with an alkaline or alkaline-earthhydroxide in aqueous or alcoholic aqueous solution followed byacidification. In a compound of formula (I) wherein R is an esterifiedcarboxy and R₁ is acyloxy, the optional saponification may be carriedout selectively with respect to the esterified carboxy, if desired, bytransesterification, i.e., by reacting it in the same alcohol whichesterifies the carboxy groups and in the presence of a base such as analkaline or alkaline-earth alkoxide or K₂ CO₃.

The optional conversion of a compound of formula (I) wherein R₁ ishydroxy into a compound of formula (I) wherein R₁ is C₁ -C₆ alkoxy oraralkoxy, if desired, may be carried out by the usual methods of theetherification, for example as described above for the etherification ofa compound of formula (I) wherein one of R₂ and R₅ is hydroxy.

When it is desired to etherify only one of several hydroxyl functionspresent it is useful to protect before the etherification the hydroxygroups which it is desired to not etherify, e.g., with the knownprotecting groups above mentioned, then removing these at the end of theetherification by the procedures already described above.

The optional conversion of a compound of formula (I) wherein R is a freeor esterified carboxy group into a compound of formula (I) wherein R is--CH₂ --OH, if desired, may be carried out, e.g., by reducing the esterwith LiAlH₄ in ethyl ether or tetrahydrofuran at reflux temperature.

The optional conversion of a compound of formula (I) wherein R is a freecarboxy group into a compound of formula (I) wherein R is ##STR31##wherein R_(a) and R_(b) are as defined above, may be performed bytreatment with an amine of formula NHR_(a) R_(b) in the presence of acondensing agent, e.g., a carbodiimide such as dicyclohexylcarbodiimide,and the optional conversion of a compound of formula (I) wherein R is anesterified carboxy into a compound of formula (I) wherein R is ##STR32##may be effected by treatment with an amine of formula NHR_(a) R_(b) in asuitable organic solvent at reflux temperature for 2-3 hours.

The optional conversion of a compound of formula (I) wherein R is a freecarboxy group into a compound of formula (I) wherein R is a radical##STR33## may be carried out by converting the carboxy group into thecorresponding halide, preferably chloride, e.g., by reaction withthionyl chloride or oxalyl chloride in dioxane or dichloroethane atreflux temperature, then reacting the halide, e.g., with ammonia, togive the amide, dehydrating the amide to nitrile, e.g., withp-toluensulphonylchloride in pyridine at approximately 90°-100° C., andfinally reacting the nitrile with sodium azide and ammonium chloride indimethylformamide at a temperature varying between the room temperatureand 100° C. But preferably the hereabove reported conversions of thecarboxy group into --CN or ##STR34## are performed on the startingmaterials i.e. for example on the compounds of formula (II) and (VI).

The optional salification of a compound of formula (I) may be performedin a conventional manner.

Also the optional separation of the optically active compounds from aracemic mixture as well as the optional separation of thediastereoisomers or of the geometrical isomers from their mixtures maybe effected by conventional methods.

The compounds of formula (II) are already known compounds and may beprepared, e.g., as described by E. J. Corey et al, Ann. of New YorkAcad. of Sciences, 180, 24 (1971), by J. Fried et al, J. Med. Chem. 16,429 (1973), G. L. Bundy et al, Amer. Chem. Soc. 94, 2124 (1972), byGandolfi et al, 11 Farmaco Ed. Sc. 27, 1125 (1972), in U.S. Pat. No.3,935,254, Derwent Farmdoc 20717X, in the German Offenlegunsschrift No.26 11 788 (Derwent Farmdoc 61615X), in the German OffenlegungsschriftNo. 26 10 503 (Derwent Farmdoc 59715X), in the GermanOffenlegungsschrift No. 26 27 422 (Derwent Farmdoc 85028X), in the U.S.Pat. No. 3,706,789, in the U.S. Pat. No. 3,728,382, in the U.S. Pat. No.3,903,131, in the U.S. Pat. No. 3,962,293, in the U.S. Pat. No.3,969,380, Derwent Farmdoc 73279U, Derwent Farmdoc 31279T, in the U.S.Pat. No. 3,890,372, in the U.S. Pat. No. 3,636,120, in the U.S. Pat. No.3,883,513, in the U.S. Pat. No. 3,932,389, in the U.S. Pat. No.3,932,479, Derwent Farmdoc 19594W, Derwent Farmdoc 54179U and in theBritish Pat. No. 1,483,880.

The compound of formula (III) wherein Q is halogen may be obtained bythe same reaction described above for the synthesys of the compound offormula (I) wherein Z₁ is halogen.

The compound of formula (III) wherein Q is a group Hg.sup.(+) Z.sup.(-)wherein Z.sup.(-) is as defined above may be prepared by cyclizing acompound of formula (II) in the presence of a source of Hg(⁺⁺) ions.

Suitable sources of Hg.sup.(++) ions may be, e.g., either compounds offormula Hg(Z)₂ or compounds of formula Hg(OH)Z.

The above cyclization may be performed, e.g., using 1.01 to 1.5,preferably 1.2, equivalents of the mercuric compound for each mole ofthe compound of formula (II), in an organic solvent miscible with water,e.g., tetrahydrofuran, methanol, ethanol or in a mixture of the organicsolvent and water. The reaction temperature may vary between 0° C. andthe boiling point of the reaction mixture and the reaction time rangesfrom about 5 minutes to about 2 hours. The cyclization gives a mixtureof four diastereoisomers of formula (III) differing from each other forthe configuration (endo or exo) of the side chain linked to theheterocyclic ring B or for the configuration (S or R) of the Qsubstituent.

The separation of the diastereoisomers from their mixture, which may becarried out according to known methods, e.g., those already describedabove, may be effected at this point or, if desired, after the reductionof the compound of formula (III).

The compound of formula (IV) wherein Z₁ is halogen may be prepared byhalocyclization of a compound of formula (VI) ##STR35## wherein R", p,q, D and R'₁ are as defined above and C is a protected aldehydic groupor a protected --CH₂ OH group, preferably a member selected from thegroup consisting of ##STR36## wherein R₁₀ is C₁ -C₆ alkyl; ##STR37##wherein n₃ is an integer of 2 to 4, preferably 2 or 3; --CH₂ --O--CH₂--C₆ H₅ or --CH₂ --O--CH₂ SCH₃, followed by the removal of theprotecting groups and by the selective oxidation of --CH₂ OH, whenobtained, to --CHO.

The halocyclization of the compound of formula (VI) may be performedusing the same reaction conditions described above for the conversion ofa compound of formula (II) into a compound of formula (I) wherein Z₁ ishalogen.

The removal of the protecting group from the aldehydic or alcoholicfunctions may be carried out by mild acid hydrolysis in the sameconditions already described in this specification for the removal ofthe protecting groups (i.e. ether groups) of the hydroxylic functions.The selective oxidation of --CH₂ OH to --CHO may be effected in aconventional manner, e.g. by treatment with an excess of at least 3moles per mole of primary alcohol of dicyclohexylcarbodiimide inbenzene-dimethylsulphoxide and in the presence of an acid catalyst,e.g., pyridine trifluoroacetate or phosphoric acid.

The compound of formula (IV) wherein Z₁ is hydrogen may be preparedeither by the dehalogenation of a compound of formula (IV) wherein Z₁ ishalogen according to the method reported above for the conversion of acompound of formula (I) wherein Z₁ is halogen into a compound of formula(I) wherein Z₁ is hydrogen or by a process comprising the cyclization ofa compound of formula (VI) in the presence of a source of Hg.sup.(++)ions [as already described for the preparation of a compound of formula(III) wherein Q is Hg.sup.(+) Z.sup.(-) ] and the subsequent reductionof the obtained compound using the same reaction conditions employed forthe reduction of a compound of formula (III).

The compound of formula (V) wherein E is ##STR38## may be prepared bytreatment of a phosphonate of formula (VII) ##STR39## wherein R_(e), Z₂,n₁, R₃, R₄, X, n₂ and R₆ are as defined above, with at least anequivalent of a base preferably selected from the group consisting of analkaline or alkaline-earth hydride, e.g., sodium, potassium, lithium orcalcium hydride; an alkaline alkoxide, e.g., sodium or potassiumtert.butoxide; an alkaline or alkaline-earth metal amide, e.g., sodiumamide; an alkaline or alkaline-earth derivative of a carboxy-amide,e.g., sodium acetamide or sodium succinimide.

The compound of formula (V) wherein E is (C₆ H₅)₃ P--.sup.(+) may beprepared by reacting a compound of formula (VIII) ##STR40## wherein Z₂,n₁, R₃, R₄, X, n₂, R₆ are as defined above and Hal is a halogen atom,with 1-1.2 molar equivalent of triphenylphosphino in an inert organicsolvent such as e.g. benzene, acetonitrile, diethylether, then treatingthe triphenylphosphonium halide so obtained with an equivalent amount ofan inorganic base such as, for example, NaOH, KOH, Na₂ CO₃, NaHCO₃.

The compound of formula (VI) may be prepared, e.g., according toTetrahedron Letters No. 42, 4307-4310 (1972).

The compound of formula (VII) wherein Z₂ is halogen may be obtained byhalogenating a compound of formula (VII) wherein Z₂ L is hydrogen in aconventional manner, operating substantially as in the halogenation ofβ-ketoesters.

The compounds of formula (VII) wherein Z₂ is hydrogen may be prepared byknown methods, e.g. according to E. J. Corey et al, J. Am. Chem. Soc.90, 3247 (1968) and E. J. Corey and G. K. Kwiatkowsky, J. Am. Chem.Soc., 88, 5654 (1966).

The compounds of formula (VIII) are known compounds or may be preparedby known methods.

The compounds of the invention can be used, in general, for the sametherapeutic indications as the natural prostaglandins in either human orveterinary medicine.

In particular, those having an acetylene bond in the 13,14-positioninstead of an ethylene and those with mono and di-substituents such asmethyl and fluorine groups have the advantages of superior resistance todegradation by the 15-PG-dehydrogenase enzymes, which quickly inactivatenatural compounds, and, of a more selective therapeutic action, asindicated below.

In order to obtain a preliminary biological profile, i.e., to assesswhether the compounds of the invention possess PC-like or thromboxane(TXA₂)-like or PGX-like activity, they were at first tested by asuperfusion cascade technique by the method of Piper and Vane, Nature223, 29 (1969).

In order to increase the sensitivity of the bioassay, a mixture ofantagonists [Gilmore et al. Nature 218, 1135 (1968)] is added to theKrebs-Henseleit and indomethacin (4 μg/ml) is also added to prevent theendogenous biosynthesis of prostaglandins.

Contraction of rat colon (RC), rat stomach strip (RSS) and bovinecoronary artery (BCA), and relaxation of rabbit mesentery artery (RbMA)are assumed to represent prostaglandin-like activity. TXA₂ -likeactivity is indicated when RbMA is contracted and must be confirmed byin vitro platelet pro-aggregation activity, since PGF₂α -like compoundsalso contract RbMA, as opposed to PGE. Finally, PGX-like activity isindicated by the relaxation of BCA, and is confirmed by in vitroplatelet anti-aggregation activity.

Synthetic PGE₂ and both the biosynthetic TXA₂ and PGX are utilized asstandard compounds.

They are active at a range of concentrations from 1-5 μg/ml.

The compounds of the invention were dissolved in a few drops of ethanoljust before testing; the stock solution was prepared in 0.1 Mtris-buffer, pH 9.0, (1 mg/ml) and diluted with Krebs-Henseleit to therequired concentration.

The compound 13-trans-11α,15S-dihydroxy-6βH-6,9α-oxide-prostenoic acidwas taken as the parent compound and is called 6βH-6,9α-oxide; thediastereoisomer 13-trans-11α,15S-dihydroxy-6αH-6,9α-oxide-prostenoicacid is then referred to as 6αH-6,9α-oxide. The chemical names of theother tested compounds are also referred to those of the parentcompounds. The compounds were tested at concentrations up to 100 ng/ml.

The results obtained showed that, in general, the 6βH-diastereoisomers,e.g., the compounds 6βH-6,9α-oxide, dl-6βH-5-bromo-6,9α-oxide,6βH-6,9α-oxide-16-m-CF₃ -phenoxy-ω-tetranor and6βH-6,9α-oxide-16-m-chloro-phenoxy-ω-tetranor possess BCA-relaxingactivity and therefore have PGX-like activity.

Among the 6βH-derivatives, only the compounddl-6βH-6,9α-oxide-16-methyl-16-butoxy-ω-tetranor showed aBCA-contracting activity. The 6αH-derivatives, e.g. the compound6αH-6,9α-oxide, dl-6αH-5-bromo-6,9α-oxide,dl-6αH-6,9α-oxide-16-methyl-16-butoxy-ω-tetranor,6αH-6,9α-oxide-16-m-CF₃ -phenoxy-ω-tetranor and6αH-6,9α-oxide-16-m-chloro-phenoxy-ω-tetranor also showedBCA-contracting activity.

In general, the exo-configuration is associated with BCA contraction.Furthermore, the compounds of the invention have hypotensive activity inmammals as does the natural compound PGX. However, as compared to PGX,they have the great advantage of a higher chemical stability and can beused in pharmaceutical formulations.

The hypotensive activity was demonstrated by the limb perfusion test.During the perfusion of the rat's left leg, through the left femoralartery, with a constant perfusion pressure, both the 6βH- and6αH-6,9α-oxide compounds caused a lowering of the values of the meanperfusion pressure at all the doses, over the range from 0.05-1 μg (to-42.5% for 6βH and -32% for 6αH). Moreover, the systemic pressure, bothsystolic and diastolic, was depressed from 0.05 μg/kg up to 5 μg/kg(about -45%).

Because of their hypotensive and vasodilatory activity, the compounds ofthe invention are useful for treatment of cases of gangrene of the lowerlimbs. For this therapeutic use they have been found to be more activethan PGE₁ and PGE₂. They are also useful in disturbances of theperipheral vasculature and, therefore in the prevention and treatment ofdiseases such as phlebitis, hepato-renal syndrome, ductus arteriosus,non-obstructive mesenteric ischemia, arteritis and ischemic ulcerationsof the leg.

Among the compounds of the invention, in particular, the 6βH-derivativesalso have a high anti-aggregating activity.

Among the 6βH compounds, the more important ones are, in order ofincreasing potency, compounds dl-6βH-5-bromo-6,9α-oxide,6βH-6,9α-oxide-16-m-CF₃ -phenoxy-ω-tetranor, dl-6βH-6,9α-oxide, and6βH-6,9α-oxide.

Using platelet-rich plasma (PRP) from healthy human donors who had nottaken any drugs for at least one week, and monitoring plateletaggregation by continous recording of light transmission in a Bornaggregometer [Born G.V.R., Nature (London) 194, 927 (1962)] there isevidence that the compounds 6βH-6,9α-oxide, dl-6βH-5-bromo-6,9α-oxide,6βH-6,9α-oxide-16-m-CF₃ -phenoxy-ω-tetranor and6βH-6,9α-oxide-16-m-chloro-phenoxy-ω-tetranor mimic the biosynthetic PGXin its platelet-antiaggregating properties. The compounds investigatedwere incubated for 2-3 minutes at 37° C. in the PRP prior to theaddition of the aggregating agents, arachidonic acid (0.4 mM), ADP (10μM), collagen (38 μM) or adrenaline (15 μM). The potency ratio for thecompound is, e.g., 1:10 for arachidonic acid-induced aggregation and1:100 for ADP-induced aggregation, as compared with biosynthetic PGX.

A very interesting increase in the anti-aggregating potency follows20-methyl substitution in both the 6βH- and 6αH-6,9α-oxide parentcompounds. Similarly, 6βH-5-bromo-20-methyl, 6βH-5,14-dibromo,6βH-13,14-didehydro-20-methyl and finally 6βH-5-bromo-13,14-didehydrocompounds and their 6βH-5-iodo (but not 6αH-5-iodo isomers) are veryactive compounds as anti-aggregating agents.

The compounds of the invention are, therefore, particularly useful inmammals for inhibiting platelet aggregation, for preventing andinhibiting thrombus formation and for decreasing the adhesiveness ofplatelets.

Therefore, they are useful in treatment and prevention of thromboses andmyocardial infarct, in treatment of atherosclerosis, and in general inall syndromes etiologically based on or associated with lipid imbalanceor hyperlipidemia, as well as in treatment of geriatric patients forprevention of cerebral ischemic episodes, and in long-term treatmentafter myocardial infarct.

When the compounds of the invention are given as anti-aggregatingagents, the routes of administration are the usual ones, oral,intravenous, subcutaneous, intramuscular. In emergency situations, thepreferred route is intravenous, with doses that can vary from 0.005 toabout 10 mg/kg/day. The exact dose will depend on the condition of thepatient, his weight, is age and the route of administration.

The compounds of the invention were also studied for their uterinecontractile activity, both in vitro and in vivo, against PGF₂α asstandard.

For example, in vitro, on the uterus of the estrogenized rat, compounds6αH-6,9α-oxide-16-m-chloro-phenoxy-ω-tetranor and6βH-6,9α-oxide-16-m-CF₃ -phenoxy-ω-tetranor, were 1.3 and 3.1 times asactive as PGF₂α. In the in vivo assay, measuring the intrauterinepressure of the ovariectomized rabbit, the same compounds were 5.9 and8.25 times as active as PGF₂α (see the following Table)

    ______________________________________                                                     in vitro                                                                      Uterus  Ileum     in vivo                                        ______________________________________                                        PGF.sub.2α                                                                             1         1         1                                          6αH-6,9α-oxide-16-m-                                                             1.3       0.05      5.9                                        chloro-phenoxy-ω-te-                                                    tranor                                                                        6βH-6,9α-oxide-16-m-                                                              3.1       0.1       8.25                                       CF.sub.3 -phenoxy-ω-tetra-                                              nor                                                                           ______________________________________                                    

The table shows that the compounds have greater activity on the uterusthan on the gastrointestinal tract.

These compounds, which are useful for induction of labor, for expulsionof dead fetuses from the pregnant female, in either human or veterinarymedicine, are without undesirable side effects of the naturalprostaglandins, such as vomiting and diarrhea.

For this purpose the compounds of the invention can be given byintravenous infusion, at a dose of about 0.01 μg/kg/minute until the endof labor. At the same dosage, the compounds of the invention dilate theuterine cervix, facilitating therapeutic abortion and, in that situationare given preferably in the form of vaginal tablets or suppositories.

The compounds of the invention, in particular the compounddl-6βH-6,9α-oxide-16-m-chloro-phenoxy-ω-tetranor also have luteolyticactivity and are therefore of use for control of fertility.

The 6βH-6,9α-oxide and their 6αH-isomers were also investigated fortheir action on the gastrointestinal tract, in order to know: (a)cytoprotective activity against lesions induced by non-steroidanti-inflammatory drugs; (b) ability to prevent the ulcers induced bythe method of Togagi-Okabe [(Japan J. Pharmac. vol. 18, 9 (1968)] and(c) antisecretory activity, according to Shay et al Gastroenter. 26, 906(1954).

The cytoprotective ability is a common feature of all the compounds. Forexample, given subcutaneously, the 6βH-6,9α-oxide is slightly moreactive (1.5-2 times) than the standard PGE₂ as a gastric antisecretoryagent.

In general, the cytoprotective activity of the 6βH compounds is doubledwhen an acetylene bond is present in the 13,14-position; it isquadrupled when a 16-alkyl group, usually a methyl, is positioned in the16(S)-configuration.

As an ulcer-preventing substance, the parent: 6βH-6,9α-oxide analog isat least equipotent with PGE₂ and the following substitutions,13,14-acetylene bond; 16S, or R methyl; 16S, or R fluoro, highlyincrease (up to 30 times) the potency ratio.

Furthermore, a significant oral antisecretory activity appears when amethyl group is in the C-15-position of the parent 6βH-6,9α-oxide or inthe 16,16-dimethyl compounds, such as the6βH-6,9α-oxide-16-methyl-16-butoxy-ω-tetranor derivative.

For this purpose the compounds are preferably given by intravenousinjection or infusion, subcutaneously or intramuscularly. Forintravenous infusion, the doses vary from about 0.1 μg to about 500μg/kg/body weight/minute. The total daily dose, either by injection orby infusion, is of the order of 0.1 to 20 mg/kg, the exact dosedepending on the age, weight and condition of the patient or of theanimal being treated and on the route of administration.

In addition, the compounds are also useful for treatment of obstructivepulmonary diseases such as bronchial asthma, since they haveconsiderable bronchodilatory activity.

For treatment of the obstructive pulmonary disorders, for examplebronchial asthma, the compounds of the invention can be given bydifferent routes: orally in the form of tablets, capsules, coatedtablets or in liquid form as drops or syrups; rectally in suppositories;intravenously, intramuscularly or subcutaneously; by inhalation, asaerosols or solutions for the nebulizer; by insufflation, in powderedform.

Doses of the order of 0.01-4 mg/kg can be given from 1 to 4 times a day,with the exact dose depending on the age, weight, and condition of thepatient and on the route of administration. For use as an antiasthmatic,the compounds of the invention can be combined with other antiasthmaticagents, such as sympathicomimetic drugs like isoproterenol, ephedrine,etc., xanthine derivatives, such as theophylline and aminophylline, orcorticosteroids.

The dosages when used as hypotensive and vasodilatory agents are aboutthe same as those used for the anti-aggregating effects. As previouslystated, the compounds of the invention can be given, either to humans oranimals in a variety of dosage forms, e.g., orally in the form oftablets, capsules or liquids; rectally, in the form of suppositories;parenterally, subcutaneously or intramuscularly, with intravenousadministration being preferred in emergency situations; by inhalation inthe form of aerosols or solutions for nebulizers; in the form of sterileimplants for prolonged action; or intravaginally in the form, e.g., ofbougies. The pharmaceutical or veterinary compositions containing thecompounds of the invention may be prepared in conventional ways andcontain conventional carriers and/or diluents.

For example, for intravenous injection or infusion, sterile aqueousisotonic solutions are preferred. For subcutaneous or intramuscularinjection, sterile solutions or suspensions in aqueous or non-aqueousmedia may be used; for tissue implants, a sterile tablet or siliconerubber capsule containing or impregnated with the compound is used.

Conventional carriers or diluents are, for example, water, gelatine,lactone, dextrose, saccharose, mannitol, sorbitol, cellulose, talc,stearic acid, calcium or magnesium stearate, glycol, starch, gum arabic,tragacanth gum, alginic acid or alginates, lecithin, polysorbate,vegetable oils, etc.

For administration by nebulizer, a suspension or a solution of thecompound of the invention, preferably in the form of a salt, such as thesodium salt in water, can be used. Alternatively, the pharmaceuticalpreparation can be in the form of a suspension or of a solution of thecompound of the invention in one of the usual liquefied propellants,such as dichlorodifluoromethane or dichlorotetrafluoroethane,administered from a pressurized container such as an aerosol bomb. Whenthe compound is not soluble in the propellant it may be necessary to adda co-solvent, such as ethanol, dipropylene glycol and/or a surfactant tothe pharmaceutical formulation.

The invention is illustrated by the following examples, wherein theabbreviations ""THF", "DME", "DMSO", "THP", "Et₂ O" refer totetrahydrofuran, dimethoxyethane, dimethylsulphoxide, tetrahydropyranyl,and ethyl ether, respectively.

The following examples illustrate but do not limit the presentinvention.

EXAMPLE 1

To a solution of 1.0 g ofdl-5β-hydroxymethyl-2α,4α-dihydroxy-cyclopentan-1α-aceticacid-γ-lactone-4-p-phenyl benzoate in 8 ml of benzene/DMSO (75/25) isadded with stirring 0.89 g of dicyclohexylcarbodiimide. Atroomtemperature, 1.42 ml of a solution of pyridinium trifluoroacetate isadded (prepared from 1 ml of trifluoroacetic acid and 2 ml of pyridinebrought to 25 ml with 75/25 benzene/DMSO). After 3 hours 19 ml ofbenzene is addedand the mixture is treated dropwise with an oxalic aciddihydrate solution,0.3 g in 3.8 ml of water. After approximately 15minutes of stirring, the mixture is filtered, and the organic phase iswashed with water until neutral, concentrated to 2 ml, and then dilutedwith 5 ml of isopropyl ether. The products is isolated by filtration andcrystallized from isopropyl ether to give 0.8 g ofdl-5β-formyl-2α,4α-dihydroxy-cyclopentan-1α-aceticacid-γ-lactone-4-p-phenylbenzoate, m.p.=129°- 131° C. A solution of 800mg of this in 2.8 ml of anhydrous methanol is treated with 0.62 ml ofmethyl orthoformate and 18 mg of p-toluenesulfonic acid monohydrate.After 1 hour, 0.01 ml of pyridine is added and the solution isevaporated to dryness. The residue is dissolved in ethyl acetate; itiswashed with 0.1 N NaOH and then saturated NaCl until neutral. Thesolvent is removed at reduced pressure and the residue is crystallizedfrom methanol to give 800 mg ofdl-5β-dimethoxymethyl-2α,4α-dihydroxy-cyclopentan-1.alpha.-aceticacid-γ-lactone-4-p-phenylbenzoate, m.p.=108°-110° C.

60 mg of K₂ CO₃ is added to a solution of this in 5.6 ml of anhydrousmethanol. After 4 hours of stirring at room temperature, the solution isfiltered; it is then reduced to small volume and acidified with asaturated NaH₂ PO₄ solution. The methanol is removed and the residuetaken up in ethyl acetate. This is washed with saturated NaCl untilneutral, is dried over anhydrous Na₂ SO₄, is filtered, andevaporatedunder reduced pressure to give 480 mg ofdl-5β-dimethoxymethyl-2α,4α-dihydroxy-cyclopentan-1.alpha.-aceticacid-γ-lactone.

A solution of this in 4 ml of CH₂ Cl₂ is treated with 0.32 ml of2,3-dihydropyran and 4.8 mg of p-toluenesulfonic acid. After 4 hours atroom temperature, pyridine is added and the solution is evaporated atreduced pressure. The crude reaction product is filtered on 5 g ofsilica gel, with cyclohexane:ethylether (50:50) as eluent, to give 380mg of dl-5β-dimethoxymethyl-2α,4α-dihydroxy-cyclopentan-1.alpha.-aceticacid-γ-lactone-4-tetrahydropyranyl ether. Starting from a 4-ester of5β-dimethoxymethyl-2α,4α-dihydroxy-cyclopentan-1α-acetic acid-γ-lactone(for example: 4-p-phenylbenzoate, m.p. 128°-130° C., [α]_(D) =-85°) orfrom a 4-ester of5α-hydroxymethyl-2β,4β-dihydroxy-cyclopentan-1β-acetic-γ-lactone (forexample: the 4-p-phenylbenzoate, m.p.=127°-129° C., [α]=+84.5°), thesame procedure was used to prepare the following compounds:5β-dimethoxymethyl-2α,4α -dihydroxy-cyclopentan-1α-aceticacid-γ-lactone-4-tetrahydropyranyl ether and5α-dimethoxymethyl-2β,4β-dihydroxy-cyclopentan-1β-aceticacid-γ-lactone-4-tetrahydropyranyl ether. If 1,4-diox-2-ene is usedinstead of 2,3-dihydropyran, the corresponding 4-dioxanyl etherderivatives are obtained.

EXAMPLE 2

A solution of 216 mg of5β-dimethoxymethyl-2α,4α-dihydroxy-cyclopentan-1α-acetic acid-γ-lactone[α]_(D) =-16°, [α]₃₆₅° =-48° (C=1.0 CHCl₃) in 1.6 ml ofdimethylformamide is treated with 0.3 ml of triethylamine followed by291 mg of dimethyl-tertbutylchlorosilane. After one hour, the mixture isdiluted with 8.3 ml of water and extracted with hexane. The organicphase is washed with water and dried over Na₂ SO₄ to give 310 mg of5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-aceticacid-γ-lactone-4-dimethyl-tert-butylsilyl ether.

EXAMPLE 3

To a solution ofdl-5β-hydroxymethyl-2α,4α-dihydroxycyclopentan-1α-propanoicacid-γ-lactone-4p-phenylbenzoate (1 g) in 8 ml of benzene:DMSO (75:25)is added 0.86 g of dicyclohexyl-carbodiimide followedby 1.37 ml of afreshly prepared pyridinium trifluoroacetate (see example 1). Afterthree hours, 18 ml of benzene is added; a solution of 0.29 g of oxalicacid dihydrate in 3.7 ml of water is then added dropwise. After 15minutes of stirring, the dicyclohexylurea is removed by filtration andtheorganic phase is washed with water until neutral. This is thenreduced to volume to approximately 2 ml and isopropyl ether is added.One obtains 0.793 g ofdl-5β-formyl-2α,4α-dihydroxycyclopentan-1α-propionicacid-δ-lactone-4-phenylbenzoate.

A solution of 780 mg of this in 2.7 ml of anhydrous methanol is treatedwith 0.59 ml of methylorthoformate and 17.3 mg of p-toluenesulfonicacid. After approximately one hour, 0.01 ml of pyridine is added and thesolution is evaporated to dryness. The residue is taken up in ethylacetate; the organic phase is washed with 1 N NaOH and then saturatedNaCluntil neutral. Evaporation to dryness gives 769 mg ofdl-5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-propionicacid-δ-lactone-4p-phenylbenzoate. This is then dissolved in 5.4 ml ofanhydrous methanol and 75 mg of K₂ CO₃ is added. After four hours ofstirring at room temperature and filtration, the solution is reduced involume and acidified with a saturated solution of NaH₂ PO₄. The methanolis evaporated and the aqueous phase treated with ethyl acetate; theorganic phase is then washed with a saturated NaCl solution untilneutral, dried over Na₂ SO₄, and evaporated under vacuum to give crudedl-5β-dimethoxymethyl-2α ,4α-dihydroxycyclopentan-1α-propanoicacid-δ-lactone. A solution of this in 4 ml of CH₂ Cl₂ is treated with0.3 ml of 2,3-dihydropyran and 4.5 mg of p-toluenesulfonic acid. Afterfour hours atroom temperature, 0.01 ml of pyridine is added and thesolution is evaporated to dryness. The reaction product is purified onsilica gel withcyclohexane: ethyl ether (50:50) as eluent to give 480 mgof dl-5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-propanoic acid-δ-lactone-4-tetrahydropyranyl ether.

From a 4-ester of5β-hydroxymethyl-2α,4α-dihydroxycyclopentan-1α-propanoic acid-δ-lactoneand from a 4-ester of5α-hydroxymethyl-2β,4β-dihydroxycyclopentan-1β-propanoic acid-δ-lactone(for example, the 4-p-phenylbenzoate), using the same procedure, thefollowing compounds were obtained:

5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-propanoicacid-δ-lactone-4-tetrahydropyranyl ether;

5α-dimethoxymethyl-2β,4β-dihydroxycyclopentan-1β-propanoicacid-δ-lactone-4-tetrahydropyranyl ether.

If 1,4-diox-2-ene is used instead of 2,3-dihydropyran, the corresponding4-dioxyanyl ether derivatives are obtained.

EXAMPLE 4

A solution of 1 g of 5β-formyl-2α-hydroxycyclopentan-1α-aceticacid-γ-lactone in 6.5 ml of anhydrous methanol is treated with 1.74 mlof methylorthoformate and 52 mg of p-toluenesulfonic acid. Afterapproximately one hour, 0.04 ml of pyridine is added and the solution isevaporated to dryness. The residue is taken up in ethyl acetate, and thewashed with 1 N NaOH and then saturated NaCl until neutral. Evaporationunder vacuum gives 1 g of5β-dimethoxymethyl-2α-hydroxycyclopentan-1α-acetic acid-γ-lactone,[α]=-16°.

The same procedure gave5β-dimethoxymethyl-2α-hydroxycyclopentan-1α-propionic acid-δ-lactone andits dl derivatives from 5β-formyl-2α-hydroxycyclopentan-1α-propionicacid-δ-lactone.

EXAMPLE 5

To a solution of 960 mg ofdl-5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-aceticacid-γ-lactone-4-tetrahydropyranyl ether in 16 ml of toluene,cooled to-70° C., is added 8.5 ml of a 0.5 N toluene solution ofdi-iso-butylaluminum hydride, over a 30 minute period. After a further30 minutes of stirring at -70° C., 10 ml of a 2 M toluene solution ofisopropanol is added dropwise. The solution is warmed to 0° C. andtreated with 3 ml of a 30% solution of NaH₂ PO₄. After 1 hourofstirring, 12 g of anhydrous Na₂ SO₄ is added. Filtration andevaporation of solvent give 900 mg of dl-5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-ethanal-γ-lactol-4-tetrahydropyranylether.

EXAMPLE 6

Following the procedure of example 5, a solution of 400 mg of5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-aceticacid-γ-lactone-4-dimethyl-tert-butylsilyl ether in 11 ml of toluene,cooled to -70° C., is treated dropwise with 5.9 ml of a 0.5 N toluenesolution of di-iso-butylaluminum hydride to give 0.43 g of5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-ethanol-γ-lactol-4-dimethyl-tert-butylsilylether.

EXAMPLE 7

Under a nitrogen atmosphere, a solution of 628 mg of5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-propanoicacid-δ-lactone-4tetrahydropyranyl ether in 11 ml of toluene, cooled to-70° C., is treated dropwise with 5.9 ml of a 0.5 M toluene solution ofdi-iso-butylaluminum hydride. After 30 minutes at -70° C., 10.9 ml of a2 M toluene solution of isopropanol is added dropwise. The temperatureis allowed to rise to 0° C. and 2 ml of 30% NaH₂ PO₄ is added. After onehour of stirring, 8.3 g of anhydrous Na₂ SO₄ is added and the mixture isfiltered. Evaporation of the organic phase under vacuum gives 620 mg of5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-propanal-δ-lactol-4-tetrahydropyranylether.

EXAMPLE 8

Using one of the procedures outlined in examples 5, 6 and 7, a 4-acetal(4-tetrahydropyranyl ether; 4-dioxanyl ether) and a 4-dimethylbutylsilylether of the following compounds are prepared:

5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-ethanal-γ-lactol, inits dl and optically active form (or nat-);

5α-dimethoxymethyl-2⊕,4β-dihydroxycyclopentan-1β-ethanal-γ-lactol (orent- form);

5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-propanal-δ-lactol, inits dl and optically active form (or nat-);

5α-dimethoxymethyl-2β,4β-dihydroxycyclopentan-1β-propanal-δ-lactol (orent- form).

EXAMPLE 9

0.29 ml of absolute ethanol in 3.5 ml of toluene is added dropwise to asolution of 5×10⁻³ mol of sodium (2-methoxyethoxy)aluminum hydride (1.4ml of a 70% benzene solution diluted with 5 ml of toluene) cooled to 0°C. 8.2 ml of the alanate solution so prepared is added, at -30° C., to0.98 g of dl-5β-benzyloxymethyl-2α-hydroxycyclopentan-1α-propionicacid-δ-lactone in 22 ml of toluene. After 45 minutes, excess reagentisquenched with 6 ml of a 0.5 M toluene solution of isopropanol. Themixture is warmed to 0° C., 4 ml of 30% NaH₂ PO₄ is added, and theresulting mixture is stirred for 2 hours. The inorganic salts areremoved by filtration and the solution is evaporated to dryness to give0.94 g ofdl-5β-benzyloxymethyl-2α-hydroxycyclopentan-1α-propanol-.delta.-lactol.

Using the procedure reported above, or one of those from examples 4 to7, the following compounds were prepared from their correspondingγ-lactones:

5β-benzyloxymethyl-2α-hydroxycyclopentan-1α-ethanal-.gamma.-lactol;

5β-benzyloxymethyl-2α-hydroxycyclopentan-1α-propanal-.delta.-lactol;

5β-dimethoxymethyl-2α-hydroxycyclopentan-1α-ethanal-.gamma.-lactol;

5β-dimethoxymethyl-2α-hydroxycyclopentan-1α-propanal-.delta.lactol.

EXAMPLE 10

With stirring and external cooling to maintain a reaction temperature of20°-22° C., a solution of 1.05 g of potassium tert-butylate in 10 ml ofDMSO is added dropwise to a solution of 1.8 g of4-carboxybutyl-triphenylphosphonium bromide and 0.38 g of5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-ethanal-γ-lactol-4-tetrahydroxypyranylether. After the addition, the mixture is held at room temperature for 1hour and then diluted with 16 mlof ice/water. The aqueous phase isextracted with ether (5×8 ml) and ether:benzene (70:30,5×6 ml); theorganic layers, after re-extraction with 0.5 M NaOH (2×10 ml), arediscarded. The combinedalkaline aqueous phase is acidified to pH 4.8with 30% NaH₂ PO₄ and then extracted with ethyl ether:pentane (1:1,5×15ml); from the combined organic phases, after drying over Na₂ SO₄ andsolvent removal, one obtains 0.45 g of5-cis-7-(2'α,4'α-dihydroxy-5'β-dimethoxymethylcyclopentan-1'α-yl)-hept-5-enoicacid-4'-tetrahydropyranyl ether. This in turn is converted to thecorresponding methyl ester upon treatment with diazomethane in ether. Ananalytic sample is prepared by adsorbing 100 mg of the crude product on1 g of silica gel and eluting with benzene:ethyl ether(85:15). N.M.R.##STR41##5.46 p.p.m. multiplet.

EXAMPLE 11

In an anhydrous nitrogen atmosphere, a suspension of 0.39 g of a 75% oildispersion of NaH in DMSO (13.5 ml) is heated to 60°-65° C. for 31/2hours; after cooling to room tempeature and while maintainingthereaction mixture at 20°-22° C., the following are added, in order:2.66 g of 3-carboxypropyltriphenylphosphonium bromide in 6 ml of DMSOand 0;6 g of5β-dimethoxymethyl-2α,4α-dihydroxycyclopentan-1α-propanal-δ-lactol-4-tetrahydropyranylether in 3 ml of DMSO. The mixture is stirred for 3 hours, and thendiluted with 35 ml of water. The aqueous phase is extracted with ethylether (5×12 ml) and ethyl ether:benzene (70:30, 7×12 ml); the combinedorganic extract, after re-extraction with 0.5 N NaOH (2×15 ml), isdiscarded. The combined alkaline aqueous extract is acidified to pH 4.3with 30% aqueous NaH₂PO₄ and extracted with ethyl ether:pentane (1:1) togive, after washing until neutral, drying over Na₂ SO₄, and removal ofthe solvent, 0.71 g of4-cis-7-(2'α,4'α-dihydroxy-5'β-dimethyoxymethyl-cyclopent-1'α-yl)-hept-4-enoicacid. Treatment with diazomethane affords the corresponding methylester.

EXAMPLE 12

The methyl esters of the following acids were prepared from lactols madeaccording to the procedures in examples 4 to 8 by treatment with aWittig reagent (prepared from 4-carboxylbutyl-triphenylphosphoniumbromide or 3-carboxypropyltriphenylphosphonium bromide) and successiveesterificationwith diazomethane, in their optically active or dl forms:

4-cis-7-(2'α-hydroxy-5'β-benzyloxymethylcyclopent-1'α-yl)hept-4-enoic;

4-cis-7-(2'α-hydroxy-4'β-dimethoxymethyl-cyclopent-1'α-yl)hept-4-enoic;

5-cis-7-(2'α-hydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)hept-5-enoic;

5-cis-7-(2'α-hydroxy-5'β-benzyloxymethyl-cyclopent-1'α-yl)hept-5-enoic;

5-cis-(7-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-hept-5-enoicand its 4'-dioxanyl, tetrahydropyranil anddimethyl-tert-butylsilyl)-ethers;

4-cis-7-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-hept-4-enoicand its 4'-(dioxanyl, tetrahydropyranyl anddimethyl-tert-butylsilyl)ethers;

4-cis-(2'α,4'α-hydroxy-5'β-diethoxymethyl-cyclopent-1'.alpha.-yl)-hex-4-enoicacid and its 4'-(tetrahydropyranylether;

5-cis-8-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-oct-5-enoicand its 4'-tetrahydropyranylether.

EXAMPLE 13

A solution of 1.06 g of the methyl ester of5-cis-7-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-hept-5-enoicacid-4'-tetrahydropyranyl ether in 5 ml of methanol is added to 0.84 gof mercuric acetate in methanol. After 30 minutes at room temperature, asolution of 250 mg of sodium borohydride in2 ml of water is added withstirring and external cooling. After 20 minutesof stirring, the mixtureis acidified to pH 6.5 with aqueous monosodium phosphate, the methanolis removed under vacuum, and the residue is taken up in water/ethylether. The organic phase, upon removal of the solvent, affords 1.02 g of5-(6'-oxo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether.

EXAMPLE 14

A solution of 1.59 g of4-cis-7-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-hept-4-enoicmethyl ester-4'-tetrahydropyranyl ether in 6 ml of THF is added to asolution of 1.26 g of mercuric acetate in 4 ml of water diluted with 4ml of THF. The mixture is stirred for 11/2 hours until precipitation iscomplete. 180 mg of sodium borohydride (in 2.5 ml of water) is thenadded and the resulting mixture is stirred for 30 minutes. The solutionis decanted from the precipitate, which is then washed with THF. Theaqueous/organic decanted solution is concentrated under reduced pressureand the residue extracted with ethyl acetate. The combined organicextract, after washing with water until neutral, affords upon removal ofthe solvent 0.98 g of4-(7'-exodimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether.

EXAMPLE 15

Starting from the esters prepared as described in examples 9 to 11, byreaction with a mercuric salt and subsequent reductive demercuration asdescribed in the procedures in examples 13 and 14, the followingbicyclic derivatives are obtained:

5-(6'-oxo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3' -yl)pentanoicacid methyl ester;

5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3' -yl)pentanoicacid methyl ester;

4-(7'-exo-benzyloxymethyl-2'-bicyclo[3.4.0]nonan-3' -yl)butanoic acidmethyl ester;

4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]-nonan-3' -yl)butanoicacid methyl ester;

a 7'-acetal ether (tetrahydropyranyl ether, dioxanyl ether), and a7'-dimethyl-tert-butylsilyl ether of5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)pentanoic acid methyl ester;

an 8'-acetal ether (tetrahydropyranyl ether, dioxanyl ether) and an8'-dimethyl-tert-butylsilyl ether of4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)butanoic acid methyl ester;

4-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-butanoic acid methyl ester-7'-tetrahydropyranyl ether;

5-(7'-oxa-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-pentanoic acid methyl ester-8'-tetrahydropyranyl ether.

All these compounds are obtained in the d,l-, nat- and ent-forms.

EXAMPLE 16

A solution of 0.48 g of bromine in 5 ml of methylene chloride is addeddropwise, with stirring, to a solution of 0.27 g of pyridine and 1.2 gof5-cis-7-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-hept-5-enoicacid methyl ester-4'-tetrahydropyranyl ether in 6 ml of methylenechloride, cooled to 0° C. Stirring is continued for ten minutesfollowing the addition. The organic phase is washeed with 5 ml of a pH 7buffer solution 10% in sodium thio sulfate and then with water untilneutral. After drying over Na₂ SO₄, removal of the solvent affords 1.38g of5-bromo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyran ether.

EXAMPLE 17

1.24 g of N-iodosuccinimide is added to a solution of 2 g of5-cis-7-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-hept-5-enoicacid methyl ester-4'-tetrahydropyranyl ether in 15 ml of carbontetrachloride. The mixture is stirred for 3 hours and 30 ml of ethylether is added. The organic phase is washed with 1 N Na₂ S₂ O₃ and thenwith water until neutral. Removal of the solvent affords 2.48 g of5-indo-5'-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester 7'-tetrahydropyranyl ether.

EXAMPLE 18

422 mg of N-bromosuccinimide is added with stirring to a solution of0.78 gof4-cis-7-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-hept-4-enoicacid methyl ester-4-tetrahydropyranyl ether in 11 ml of CCl₄. After fourhours of stirring, ethyl ether is added; the solution is then washedwith water, 1 N Na₂ S₂ O₃, and water until neutral. Evaporation todryness gives 0.98 g of4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether.

EXAMPLE 19

To a suspension of 0.25 g of dry CaCO₃ in a solution of 346 mg of5-cis-7-(2'α-dihydroxy-4β-benzyloxymethyl-cyclopent-1'α-yl)-hept-5-enoic acid methyl ester in 10ml of CCl₄ cooled to 0°-5° C. is added withstirring a solution of 75 mgof chloride in 3 ml of CCl₄. After stirring for 2 hours, the inorganicsalts are removed by filtration. The solution is washed with a 7%aqueous solution of KI and Na₂ S₂ O₃ and then with water until neutral.The residue upon evaporation todryness is adsorbed on silica gel andeluted with cyclohexane:ethyl ether (80:20) to give 0.27 g of5-chloro-5-(6'exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester.

EXAMPLE 20

A solution of 0.39 g of5-cis-7-(2'α,4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl)-hept-5-enoicacid methyl ester-4'-dioxanyl ether and 98 mg ofpyridine in 10 ml ofdichloromethane is cooled to -40° C. A solutionof 81 mg of chlorine in 6ml of CH₂ Cl₂ is then added over a period of 30 minutes. After 10minutes of stirring, the mixture is heated to room temperature. Theorganic phase is washed with a 7% solution of KI and Na₂ S₂ O₃ and thenwith water until neutral. Removal ofthe solvent affords 0.39 g of5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-4'-dioxanyl ether.

EXAMPLE 21

280 mg of iodine in CCl₄ is added to a solution of 0.39 g of4-cis-7-(2'α,4'α-dihydroxy-5β-dimethoxymethyl-cyclopent-1'α-yl)-hept-4-enoicacid methyl ester-4'-tetrahydropyranyl ether and 82 mg of pyridine in 10ml of CCl₄. Stirring is continued until the color disappears; 30 ml ofethyl ether is then added. The organic phase iswashed with water, then asolution 7% in KI and Na₂ S₂ O₃, and then water until neutral. Removalof the solvent affords 0.48 g of4-iodo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether.

EXAMPLE 22

To a solution of 0.34 g of5-cis-7-(2'α-hydroxy-5'β-benzyloxymethyl-cyclopent-1'α-yl)-hept-5-enoicacid methyl ester in 6 ml of methanol is added with stirringa solutionof 0.325 g of mercuric acetate in water:methanol (1:9, 6 ml). Themixture is stirred for 15 minutes, reduced to 3 ml under vacuum, andthen added to 5 ml of a saturated solution of NaCl in water. Theprecipitate is then extracted with methylene chloride. The organic phaseis washed with water and evaporated to dryness to give 0.52 g of crude5-chloromercurio-5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester. A solution of this in methylenechloride(10 ml) is treated with 80 mg of pyridine in 2 ml of CH₂ Cl₂ andthen dropwise with stirring with a solution of 150 mg of Br₂ in CH₂ Cl₂.After 20 minutes of stirring at room temperature, the organic phase iswashed with water, then 7% KI and Na₂ S₂ O₃, and water until neutral.Evaporation to dryness gives 0.34 g of5-bromo-5-(6'-exo-benzyloxymethyl-2'oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester. Mass spectrum M⁺ 424,426 m/e M⁺ -HBr344 m/e M⁺ -CHBr (CH₂)₃ CO₂ CH₃ =231m/e.

EXAMPLE 23

10.5 mg of p-toluenesulfonic acid monohydrate is added to a solution of0.26 g of5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether and theresulting mixture is left ar room tenperature for 30 minutes. 10 mg ofpyridine is then added and the solution is evaporated to dryness. Theresidue is taken up in ethyl ether/water. After drying over Na₂ SO₄, theorganic phase gives upon solvent evaporation 0.23 g ofcrude5-iodo-5-(6'exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester. Separation by chromatography onsilicagel with methylene chloride:ethyl ether (75:25) as eluent affords84 mg of3-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-pentanoicacid methyl ester and 55 mg of the 3'-exo isomer.

Referring the spectrometric data, the prostaglandin numbering will beused;thus the above diastereoisomers can be named as follows: the endodiastereoisomer:6βH-6,9α-oxide-11α-hydroxy-12β-dimethoxy-formylacetal-ω(20→13)tetranor-prostanoicacid methyl ester and the exo diastereoisomer6αH-6,9α-oxide-11α-hydroxy-12β-dimethoxy-formylacetal-ω(20→13)tetranor-prostanoicacid methyl ester.

Analytical data:

endo diastereoisomer: TLC more polar-one spot

Mass spectrum (m/e; % intensity fragment): 442 0.002 M⁺ ; 412 4 M⁺ --CH₂O, 315/314 3 M⁺ -iodine/HI 283 11 315--CH₃ OH, 75 100 ##STR42##

N.M.R. (solvent CDCl₃, TMS internal standard) p.p.m.: 3.49 and 3.52s,3H/3H, ##STR43##3.64 s,3H,CO₂ CH₃ ; 4.00 m, 3H (protons at C₅, C₉,C₁₁); 4.29 d,1H, ##STR44##4.60 m, 1H, 6βH

¹³ C-MR (at 20 MHz in C₆ D₆ solution TMS int. standard) p.p.m. 172.9,36.5, 33.1, 25.6, 41.8, 81.0, 38.1, 55.5, 83.1, 41.5, 74.2, 44.6, 108.0,54.2, 54.1, 51.0.

exo diastereoisomer: TLC less polar-one spot

Mass spectrum: 442 0.01 M⁺, 366 3 M⁺ CH₂ CH(OCH₃)₂, 315 4 M⁺ -I; 283 10M⁺ -I-CH₃ OH; 75 100 CH(OCH₃)₂ ⁺

N.M.R.: p.p.m. 3.34 and 3.37 3H/3H s ##STR45##3.5 and 4.1 m 1H and 2Hprotons at C₅,C₉,C₁₁ uncertain assignment, 3.65, s3H, CO₂ CH₃ ; 4.21,d1H, ##STR46##4.35 m, 1H,6αH ¹³ CMR; p.p.m. 173.0, 37.0, 33.1, 25.5,40.1, 84.4, 39.7, 57.2, 83.7, 40.5, 75.9, 44.0, 107.3, 54.0, 53.8, 51.1.

EXAMPLE 24

A solution of 980 mg of 4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3' -yl)-butanoic acidmethyl ester-8'-tetrahydropyranyl ether in 6 ml of anhydrous methanol istreated at room temperature for 30 minutes with 48 mg ofp-toluenesulfonicacid. 2% aqueous NaHCO₃ is added and the mixture isextracted with ethyl ether. From the organic phase, after washing untilneutral and evaporation of the solvent, one obtains 0.68 g of a crudeproduct which after purification on silica gel with methylenechloride:ethyl ether (80:20) as eluent affords 0.30 g of4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-exo-yl)-butanoicacid methyl ester and 0.29 g of the 3'-endo isomer.

EXAMPLE 25

Starting from acids prepared according to the procedure of example 11and performing their halocyclization as described in one of the examples16 to22, the following halobicyclic compounds are prepared:

5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether (and7'-dioxanyl ether and 7'-dimethylbutylsilyl ether);

4-chloro-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and8'-dioxanyl and 8'-dimethylbutylsilyl ethers);

5-chloro-5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;

5-chloro-5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;

4-chloro-4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;

4-chloro-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;

5-bromo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether (and7'-dioxanyl and 7'-dimethylbutylsilyl ethers);

4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and8'-dioxanyl and 8'-dimethylbutylsilyl ethers);

5-bromo-5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester,

5-bromo-5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;

4-bromo-4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;

4-bromo-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid-methyl ester;

5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxu-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether (and7'-dioxanyl and 7'-dimethylbutylsilyl ethers);

4-iodo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and8'-dioxanyl and 8'-dimethylbutylsilyl ethers);

5-iodo-5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;

5-iodo-5-(6'-exobenzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;

4-iodo-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;

4-iodo-4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester.

EXAMPLE 26

Selective de-acetalization or de-silylization of the ethers described inexample 25, according to the procedure in examples 23 and 24 affords the3' -oxiran-hydroxide-formyl acetales derivatives, which give thefollowingupon separation of isomers:

5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endoisomers;

4-chloro-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester, and its individual 3'-exo and 3'-endoisomers;

5-bromo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endoisomers;

endo isomer: TLC on SiO₂ more polar one spot

N.M.R. (CDCl₃) p.p.m. 3.4 d,6H, ##STR47##3.65, s,3H CO₂ CH₃ 4.00 m,4H(protons at C₄,C₅,C₉,C₁₁); 4.17 d,1, ##STR48##4.5 m,1H, 6βH

¹³ CMR: 173.0,35.0, 33.3, 23.6, 59.4, 80.6, 36.4, 55.6, 83.3, 41.6,74.3, 44.5, 108.0, 54.4, 54.2, 51.1

exo isomer: TLC on SiO₂ less polar isomer one spot

N.M.R.: (CDCl₃) p.p.m.: 3.37 d, ##STR49##3.66 s,3H,CO₂ CH₃ 4.00 m,4H,protons at C₄,C₅,C₉,C₁₁ ; 4.2 d,1, ##STR50##4.32 m,1H, 6αH

¹³ CMR: 173.0, 35.5, 33.3, 23.6, 57.7, 84.2, 38.2, 57.9, 83.6, 40.5,76.0, 43.9, 107.2, 53.8, 53.8, 51.0.

4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester and its individual isomers, 3'-exoand3'-endo;

5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3-yl)-pentanoic acid methyl ester and its individual 3'-exo and 3'-endoisomers;

4-iodo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3''-yl)-butanoicacid methyl ester and its individual 3'-exo and 3'-endo isomers.

EXAMPLE 27

With stirring under nitrogen, a benzene solution (30 ml) of 2.8 g of5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether istreatedwith a solution of 2.8 g of tributyltin hydride in 8 ml ofbenzene. The mixture is held at 55° C. for 8 hours and then overnight atroom temperature. The benzene layer is washed with 2×10 ml of a 5%NaHCO₃ solution and then with water until neutral. The residue uponsolvent evaporation is adsorbed on 10 g of silica gel and eluted withbenzene and benzene:ethyl ether (85:15) to give 1.94 g of5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether.

EXAMPLE 28

60 mg of p-toluenesulfonic acid is added to a solution of 1.98 g of5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether in 10 ml ofanhydrous methanol. After 30 minutes at room temperature, this is addedto20 ml of 20% aqueous NaHCO₃. The mixture is extracted with ethylether; the combined ether extract, after drying over Na₂ SO₄,isevaporated to dryness. The residue is adsorbed on 100 g of silica geland eluted with methylene chloride:ethyl ether (94:6) to give 0.64 g of5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoicacid methyl ester, 0.52 g of the 3'-endo isomer and 0.12 g of the 3'-yl.

N.M.R. (CDCl₃) endo isomer 4.6 p.p.m. m,1H 6βH, T.L.C. more polar; exoisomer 4.3 p.p.m. m,1H 6αH, T.L.C. less polar.

0.32 g of the 3'-endo isomer is dissolved in pyridine (0.8 ml) andtreated for 8 hours at room temperature with 0.3 ml of acetic anhydride.The mixture is then poured into ice/water, and, after acidifying to pH4.2, isextracted with ethyl ether. The combined extract, after washinguntil neutral, is evaporated to give 0.315 g of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoicacid methyl ester-7'-acetate.

EXAMPLE 29

A solution of 1.32 g of4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester-8'-tert-butylmethylsilyl ether in 10 mlofanhydrous methanol is treated with 55 mg of p-toluenesulfonic acid for2 hours at room temperature. 0.1 ml of pyridine is added, the solvent isremoved under vacuum, and the residue is taken up in water/ethyl ether.The organic phase gives, upon removal of the solvent, 1.1 g of the crude8'-hydroxy-3' -yl derivative. Chromatography of this on silica gel withbenzene:ethyl ether (80:20) as eluent separates this into4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-endo-yl)-butanoicacid methyl ester (0.42 g) and the 3'-exo-yl isomer (0.34 g).

EXAMPLE 30

Using the procedure in examples 28 and 29, methanolysis of the ethers(acetal or silyl) described in example 15 gives the corresponding freealcohols.

EXAMPLE 31

Upon acetylation with pyridine (0.6 ml) and acetic anhydride (0.3 ml)0.2 gof5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-pentanoicacid methyl ester gives 0.21 g of the corresponding7'-acetoxyderivative.

N.M.R. (CDCl₃) p.p.m.: 2.03 s,3H OCOCH₃ ; 3.36-3.40 s,s 3H/3H##STR51##3.66 s 3H CO₂ CH₃ ; 4.00 m 2H protons at C₅,C₉ ; 4.27 d1H##STR52##4.6 m 1H 6βH 5.0 m 1H proton at C₁₁

[The spectrometric data for the 6αH isomer acetate are respectively thefollowing 2.03; 3.34-338, 3.66 s+m 4H CO₂ CH₃ and one of C₅,C₉ protons4.1 m 1H other of C₅,C₉ protons 4.2, 4.4m 1H 6αH, 5.1]. A solution ofthe 5-iodo-3'-endo-acetate in benzene (5 ml) is treated with 0.4 g oftributyltin hydride for 10 hours at 50° C. After the benzene phase iswashed with 5% NaHCO₃ and water, evaporation of the solvent andpurification on silica gel (10 g) with a benzene:ethyl ether (80:20)eluent afford 0.105 g of5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-pentanoicacid methyl ester-7'-acetate, identical in all respects with a sampleprepared by the procedure in example 28.

EXAMPLE 32

Using the procedure of examples 27 and 31, the reduction withtributyltin hydride of one of the halo-derivatives synthesized inexamples 16-26 givesthe corresponding derivative in which halogen isreplaced by hydrogen. These are identical in every way with thecompounds prepared according to the procedures of examples 15, 28, 29and 30.

EXAMPLE 33

5.4 mg of hydroquinone and a solution of 1.63 g of oxalic acid in 48 mlof water are added to a solution of 4 g of5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester in 180 ml of acetone. After 12 hours at40° C., the acetone is removed at reduced pressure and the mixture isextracted with ethyl acetate (3×25 ml). The combined organic extract iswashed until neutral with a 10% ammonium sulfate solution and dried overNa₂ SO₄. Removal of the solvent affords 3.21 g of5-(6'-exoformyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)pentanoic acid methyl ester. The 6'-exo-formyl-3'-endo and the6'-exo-formyl-3'-exo derivatives are prepared from the correspondingindividual isomers.

EXAMPLE 34

Using the procedure of example 33, starting from the correspondingbicyclo[3.3.0]octan-6'-exo-dimethoxymethyl andbicyclo[3.4.0]nonan-7'-exo-dimethoxymethyl derivatives, the followingcompounds are prepared, either as individual 3'-exo and 3'-endo or 3'isomers:

5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methylester;

4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methylester;

5-(6-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoicacidmethyl ester;

4-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoicacidmethyl ester;

5-chloro-5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoicacid methyl ester;

4-chloro-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoicacid methyl ester;

5-chloro-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoicacid methyl ester;

4-chloro-4-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoicacid methyl ester;

5-bromo-5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoicacid methyl ester;

4-bromo-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acidmethyl ester;

5-bromo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoicacid methyl ester;

4-bromo-4-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoicacid methyl ester;

5-iodo-5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acidmethyl ester;

4-iodo-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acidmethyl ester;

5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoicacid methyl ester;

4-iodo-4-(7'-exo-dormyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoicacid methyl ester;

5-(3'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoicacid methyl ester-7'-acetate;

5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl-pentanoicacid methyl ester-7'-acetate;

5-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-pentanoicacid methyl ester;

4-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-butanoicaciemethyl ester.

EXAMPLE 35

To a solution of 1.2 g of5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3' -yl)-pentanoicacid methyl ester in methanol:methyl acetate (10 ml:10 ml) is added 2 mlof a 0; 1 N methanol solution of HCl. After 0.15 g of PtO₂ is added, themixture is hydrogenated at ambient temperature and pressure until 1molar equivalent of hydrogen is absorbed. After the removal of the gasunder vacuum and washing with nitrogen, the suspension is filtered,neutralized, and evaporated to dryness. The residue is taken up inwater/ethyl acetate, and the organic phase yields 0.84 g of5-(6'-exo-hydroxymethyl-2'-oxa-bicyclo[3.3.0]octan-3' -yl)-pentanoicacidmethyl ester. This is then oxidized to the 6'-exo-formyl derivativeby the procedure in example 1, using dicyclohexylcarbodiimide inDMSO:benzene (25:75).

EXAMPLE 36

To a solution of 18.1 g of5β-tetrahydropyranyloxymethyl-2α,4α-dihydroxy-cyclopent-1α-aceticacid-γ-lactone-4-tetrahydropyranyl ether in 150 ml of toluene cooled to-70° C. is added in 30 minutes 128 ml of a 5 M solution ofdi-iso-butylaluminum hydride (1.2 M/M). After 30 minutes at -70° C., 128ml of a 2 M toluene solution of isopropanol is added and the solution isbrought to 0° C. Then 10 ml of a saturated aqueous solution of NaH₂ PO₄is added and the mixture is stirredfor four hours. Following theaddition of 10 g of anhydrous Na₂ SO₄ and 10 g of filtering earth, thesolution is filtered and evaporated to dryness to give 18.1 g of5β-tetrahydropyranyloxymethyl-2α,4α-dihydroxy-cyclopent-1α-ethanal-γ-lactol-4-tetrahydropyranylether. A solution of this in 24 ml of anhydrous DMSO is added dropwiseto a solution of the ylide prepared as follows: 9.6 g of 80% sodimhydride in 300 ml of DMSO isheated for four hours at 60° C. Then afterthe mixture is brought to18°-20° C., 67 g of 4-carboxybutyltriphenylphosphonium bromide dissolved in 80 ml of anhydrous DMSO is added whilemaintaining a temperature of 20°-22° C. to generate a bright red color.After four hours of stirring, 600 ml of water is added and the mixtureis extracted with ethyl ether:benzene (70:30) to remove thetriphenylphosphine oxide. The benzene organic phase is re-extracted with0.1 N NaOH and then with water until neutral; it is then discarded. Thealkaline aqueous phase is acidified to pH 5-4.8 and then extracted withethyl ether:pentane (1:1) to give 21.6 g of5-cis-7-2'α,4'α-dihydroxy-5'β-tetrahydropyranyloxymethyl-cyclopent-1α-yl)-hept-5-enoicacid-4'-tetrahydropyranyl ether, which may be converted to its methylester by treatment with diazomethane in ether. 7.72 g of this ester in28 ml of tetrahydrofuran is added dropwise to a yellow-brown suspensionformed by adding 28 ml of THF to a solution of 6.13 g of mercuricacetate in 28 ml of water. After the mixture is stirred for 20 minutesat room temperature, it is cooled in an ice:water bath and 810 mg ofNaBH₄ in 14 ml of water is added dropwise. Elemental mercuryprecipitates out, the suspension is decanted, the tetrahydrofuran isevaporated at reduced pressure and the residue is extracted with ethylether. Removal of the solvent affords 7.5 g of5-(6'-exo-tetrahydropyranyloxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether; 0.42 gofp-toluenesulfonic acid is then added to a solution of this in 30 ml ofmethanol. After 2 hours at room temperature, the solution isconcentrated under vacuum and water is added. After extraction withether and chromatography on silica gel with ethyl ether as eluent, oneobtains 2.4 gof5-(6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoicacid methyl ester and 2.6 g of the 3'-endo isomer.

EXAMPLE 37

2.5 g of N-iodosuccinimide is added to a solution of 4.26 g of5-cis-7-(2'α,4'α-dihydroxy-5'β-tetrahydropyranyloxymethyl-cyclopent-1'α-yl)-hept-5-enoicacid-4'-tetrahydropyranyl ether in CH₂ Cl₂ :CCl₄ (10 ml:10 ml) and theresulting mixture is stirred for four hours. 30 ml of anhydrous methanolcontaining 130 mg of p-toluenesulfonic acid is added and stirring iscontinued for another 2 hours. 0.2 ml of pyridine is added, the mixtureis reduced to small volume, and the residue is taken up in water/ethylacetate. After washing with Na₂ S₂ O₃ and then water until neutral, theorganic phase is evaporated to dryness to give a residue that adsorbedon silica gel and eluted with ethyl ether to give 2.2 g of5-iodo-5-(6'-exohydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoicacid methyl ester and 1.85 g of the 3'-endo isomer.

EXAMPLE 38

Following the procedure of example 37, but using the methyl etherinstead of the acid and N-bromoacetamide instead of N-iodosuccinimide,the5-bromo-5-(6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoicacid methyl ester is prepared. Silica gel chromatography allows theseparation into the 3'-exo and 3'-endo isomers.

EXAMPLE 39

A solution of 0.86 g of pyridine and 2.2 g of5-cis-7-(2'α,4'α-dihydroxy-5'β-tetrahydropyranyloxymethyl-cyclopent-1'α-yl)-hept-5-enoicacid methyl ester-4'-tetrahydropyranyl ether in dichloromethane (20 ml)is cooled to -30° C. and 0.38 g of chlorine in 10 ml of CCl₄ :CH₂ Cl₂(1:1) is added. The mixture is stirred for 2 hours, warmed to roomtemperature, and washed with 2 N H₂ SO₄ and then water until neutral.After evaporation of the solvent, the residue is dissolved in methanol(10 ml) and treated with 0.1 g of p-toluenesulfonic acid. The solutionis then concentrated, diluted with water, and extracted with ethylacetate. Removal of the solvent and purification of the residue onsilica gel afford 0.6 g of5-chloro-5-(6'-exo-hydroxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoicacid and 0.71 g of the 3'-endo isomer.

EXAMPLE 40

To a solution of 0.356 g of5-iodo-5-(6'-exo-hydroxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoicacid methyl ester in 4.8 ml of benzene:DMSO (75:25) are added, in order,0.28 g of dicyclohexylcarbodiimide and 0.4 ml of a pyridiniumtrifluoroacetate solution (see example 1). After 3 hours of stirring, 8ml of benzene and then aqueous oxalic acid (94 mg in 1.2 ml) are added.The precipitate is removed by filtration and the benzene solution iswashed with water until neutral. Removal of the solvent affords 0.32 gof5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoicacid methyl ester.

EXAMPLE 41

Upon oxidation of the 6'-exo-hydroxymethyl-7'-endohydroxy derivativesprepared according to examples 36-39, following the procedure of example40, the corresponding 6'-exo-formyl derivatives are prepared.

EXAMPLE 42

A solution of 3.4 g of (2-oxo-heptyl)dimethoxyphosphonate in 50 ml ofdimethoxyethane is added dropwise to a suspension of 0.45 g of 80% NaH(mineral oil dispersion). After stirring for 1 hour, a solution of 2.7 gof 5-(6'-exo-formyl-7'-endohydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester in 40 ml of dimethoxyethane is added.In 10 minutes this is diluted with 50 ml of a 30% aqueous solution ofmonobasic sodium phosphate. The organic phase is separated, the aqueousphase is re-extracted, and the combined organic extract is evaporated.Purification of the crude product on 50 g of silica gel(cyclohexane:ethylether, 50:50) gives 1.1 g of5-[6'-exo-(3"-oxo-oct-1"-trans-en-1"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl]-pentanoicacid methyl ester or13t-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acid methyl esterand 0.98 g of5-[6'-exo-(3"-oxo-oct-1"-trans-en-1"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl]-pentanoicacid methyl ester or13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acid methyl ester,plus 0.9 g of a 1:1 mixture of the two isomers (3'-exo and 3'-endo, or6αH and 6βH). This last mixture is separated into its twio isomericcomponents by thin layer chromatography with ethyl ether. They show thefollowing absorptions, respectively:

λ_(max) ^(MeOH) =230 mμ, ε=13,070; λ_(max) ^(MeOH) =228 mμ, ε=12,200.

N.M.R. (CDCl₃) 0.9 t 3H C₂₀ -CH₃, 3.68 s 3H CO₂ CH₃, 6.16 d 1H vinylicproton at C₁₄ (J_(H).sbsb.14_(-H).sbsb.15 16 Hz); 6.71 q 1H vinylicproton at C₁₃ (J_(H).sbsb.13 9 Hz).

By the same procedure, from the corresponding 5-H and 5-halo compounds,thefollowing prostenoic acid derivatives are prepared:

13t-6αH-6(9α)-oxide-15-oxo-prost-13-enoic acid methyl ester;

13t-6αH-6(9α)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;

13t-6αH-6(9α)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;

13t-6αH-6(9α)-oxide-5-iodo-15-oxo-prost-13-enoic acid methyl ester;

13t-6αH-6(9α)-oxide-5-chloro-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester;

13t-6αH-6(9α)-oxide-5-bromo-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester, N.M.R.=3.67 s 3H CO₂ CH₃ ; 3.95 m 4H C₅,C₉,C₁₁ protons andHx/Hy proton at C₄ ; 4.3 m 1H 6αH; 6.15 d 1H C₁₄ proton; 6.63 q 1H C₁₃proton;

13t-6αH-6(9α)-oxide-5-iodo-11α-hydroxy-15-oxo-prost-13-enoic acid methylester, N.M.R. 0.9 s 3H C₂₀ CH₃, 3.53 m 1H proton at C₅, 3.6 s 3H CO₂ CH₃3.9 m H proton at C₄, 4.1 m 2Hproton at C₉, C₁₁ ; 4.4 m 1H 6αH; 6.2 d 1Hproton at C₁₄ 6.75 q 1H proton at C₁₃ ;

13t-6βH-6(9α)-oxide-15-oxo-prost-13-enoic acid methyl ester;

13t-6βH-6(9α)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;

13t-6βH-6(9α)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;

13t-6βH-6(9α)-oxide-5-iodo-15-oxo-prost-13-enoic acid methyl ester;

13t-6βH-6(9α)-oxide-5-chloro-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester;

13t-6βH-6(9α)-oxide-5-bromo-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester, N.M.R.: 3.65 s 3H CO₂ CH₃ ; 4.00 m 3H proton at C₅,C₉,C₁₁,1.6 m 1H 6βH; 6.2 d 1H proton at C₁₄ ; 6.64 q 1H proton at C₁₃ ;

13t-6βH-6(9α)-oxide-5-iodo-11α-hydroxy-15-oxo-prost-13-enoic acid methylester; N.M.R. 3.66 s 3H CO₂ CH₃, 3.96 m 3H protonsat C₉,C₁₁ and C₅, 4.6m 1H 6βH, 6.21 d 1H proton at C₁₄ 6.75 q 1H proton at C₁₃.

EXAMPLE 43

A solution of 2.16 g of (2-oxo-octyl)dimethylphosphonate in 20 ml ofbenzene is added dropwise to a suspension of 292 mg of NaH (75% mineraloil dispersion) in 30 ml of benzene. After 30 minutes of stirring, asolution of 2.6 g of4-bromo-4-(7'-exo-formyl-3'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester in 20 ml of benzene is added drop bydrop.Stirring is continued for another 30 minutes, and 24 ml of a 30%aqueous solution of NaH₂ PO₄ is added. The organic phase is separated,and the aqueous phase is reextracted with benzene. The organic layersare combined and evaporated to dryness. The residue is purified onsilica gel (50 g) with CH₂ Cl₂ :ethyl ether (120:40) as eluent to give0.52g of4-bromo-4-[7'-exo-(3"-oxo-oct-1"-trans-1"-enyl)-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-endo-yl]-butanoic acid methyl ester or13-trans-4-bromo-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester and 1.45 g of4-bromo-4-[7'-exo-(3"-oxo-oct-1"-trans-1"-enyl)-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-exo-yl]-butanoicacid methyl ester or13-trans-4-bromo-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester. Methanolic solutions of these two compounds absorb in theUV at λ_(max) ^(MeOH) =230 mμ, ε=10,640, and λ_(max) ^(MeOH) =229 mμ,ε=11,600, respectively.

The same procedure, starting from the 4-H and 4-halo bicycloderivatives, gives the following prostenoic acids:

13-trans-5βH-5(9α)-oxide-15-oxo-prost-13-enoic acid methyl ester;

13-trans-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoicacid methylester;

13-trans-4-chloro-5βH-5(9α)-oxide-15-oxo-prost-13-enoic acid methylester;

13-trans-4-chloro-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester;

13-trans-4-bromo-5βH-5(9α)-oxide-15-oxo-prost-13-enoic acid methylester;

13-trans-4-bromo-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester;

13-trans-4-iodo-5βH-5(9α)-oxide-15-oxo-prost-13-enoic acid methyl ester;

13-trans-4-iodo-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester;

13-trans-5αH-5(9α)-oxide-15-oxo-prost-13-enoic acid methyl ester;

13-trans-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acid methylester;

13-trans-4-chloro-5αH-5(9α)-oxide-15-oxo-prost-13-enoic acid methylester;

13-trans-4-chloro-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester;

13-trans-4-bromo-5αH-5(9α)-oxide-15-oxo-prost-13-enoic acid methylester;

13-trans-4-bromo-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester;

13-trans-4-iodo-5αH-5(9α)-oxide-15-oxo-prost-13-enoic acid methyl ester;

13-trans-4-iodo-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester.

EXAMPLE 44

By the procedure of example 42, the reaction of 620 mg of(2-oxo-3-methyl-4-butoxybutytl)phosphonate with 74 mg of NaH (75%) and0.43 g of 5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester in dimethoxyethane gives, afterchromatography on silica gel (25 g) with 1:1 ethyl ether:hexane aseluent,0.15 g of13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester (λ_(max) =238 mμ, ε=14,500) and 300 mg of the6βH-isomer (λ_(max) =237 mμ, ε=12.280).

Mass spectrum: m/e 410 M⁺, m/e 392 M⁺ --H₂ O; m/e 379 M⁺ --OCH₃ ; m/e295 M⁺ -115, m/e 115 ##STR53##The two isomers present similar spectrawith minimal differences at level of secondary fragmentation.

Using the same procedure the 5-chloro, 5-bromo and 5-iodo 13t-6H-6(9α)-oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester.

EXAMPLE 45

By the procedure of example 44, from4-(7'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester and the 4-iodo bicyclic derivative thefollowing are obtained:

13t-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester;

13t-4-iodo-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester;

13t-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester;

13t-4-iodo-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester.

EXAMPLE 46

To a suspension of 45 mg of 80% NaH in 10 ml of benzene is added asolutionof 375 mg of (2-exo-3,3-dimethyl-heptyl)dimethylphosphonate in10 ml of benzene, followed 30 minutes later by a solution of 0.305 g of5-iodo-5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3' -yl)-pentanoicacid methyl ester. After stirring for 45 minutes, the mixture is dilutedwith 10% aqueous NaH₂ PO₄. The organic phase is washed untilneutral,dried and concentrated to small volume. Adsorption on silica geland elution with cyclohexane:ethyl ether (90:10) give 0.12 g of13t-5-iodo-6βH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoicacidmethyl ester and 0.095 g of13t-5-iodo-6αH-6(9α)-oxide-15-oxo-16,16-dimethyl-13-enoic acidmethylester.

EXAMPLE 47

By substituting in the procedure of example 46 the formyl derivativesprepared according to example 34, the following 16,16-dimethylderivativesare prepared:

13t-6βH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methylester;

13t-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-5βH-5(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methylester;

13t-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-5-chloro-6βH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acidmethyl ester;

13t-5-chloro-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-4-chloro-5βH-5(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acidmethyl ester;

13t-4-chloro-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-5-bromo-6βH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoicacidmethyl ester;

13t-5-bromo-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-4-bromo-5βH-5(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoicacidmethyl ester;

13t-4-bromo-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-5-iodo-6βH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acidmethyl ester;

13t-5-iodo-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-4-iodo-5βH-5(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acidmethyl ester;

13t-4-iodo-5βH-5(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-6αH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methylester;

13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-5αH-5(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methylester;

13t-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-5-chloro-6αH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acidmethyl ester;

13t-5-chloro-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-4-chloro-5αH-5(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acidmethyl ester;

13t-4-chloro-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-5-bromo-6αH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13 enoic acidmethyl ester;

13t-5-bromo-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-4-bromo-5αH-5(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acidmethyl ester;

13t-4-bromo-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-5-iodo-6αH-6(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoicacidmethyl ester;

13t-5-iodo-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

13t-4-iodo-5αH-5(9α)-oxide-15-oxo-16,16-dimethyl-prost-13-enoicacidmethyl ester;

13t-4-iodo-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoicacid methyl ester;

EXAMPLE 48

To a suspension of 178 mg of NaH (75% mineral oil dispersion) in 15 mlof benzene is added dropwise a solution of 1.55 g of[2-oxo-3(S,R)-fluoro-4-cyclohexyl-butyl]-dimethylphosphonate in 10 ml ofanhydrous benzene. After 30 minutes of stirring, a solution of 1 g of5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester is added and stirring is continued foranother hour. The mixture is neutralized with 30% aqueous NaH₂ PO₄, andthe organic phase is separated, concentrated and adsorbed onsilica gel.Elution with CH₂ Cl₂ :Et₂ O (90:10) gives, 0.62 g of13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester (λ_(max) ^(MeOH) =238 mμ, ε=12,765) and 0.31 g ofthe6βH isomer (λ_(max) ^(MeOH) =238 mμ, ε=9,870).

The N.M.R. data for the former compound are the following (CDCl₃) p.p.m.3.64 s 3H CO₂ CH₃, 3.8 m 1H C₉ proton, 4.03 q 1H proton at C₁₁, 4.3 m 1H6αH, 5.00 and 5.55 t,t 1/2 H,1/2 H proton at C₁₆ J_(HF) 55 Hz, 6.54 q 1Hproton at C₁₄ 6.9 q 1H proton at C₁₃ J_(H).sbsb.14_(-H).sbsb.12 3.5 Hz,J_(H).sbsb.13_(-H).sbsb.12 7.5 Hz, J_(H).sbsb.13_(-H).sbsb.14 15.5Hz.

Treating this compound with pyridine and acetic anhydride it isconverted into the 11α-acetoxy derivative, for which the N.M.R. dataare: (CHCl₃) p.p.m. 2.02 s 3H OCOCH₃, 3.64 s 3H CO₂ CH₃, 3.8 proton atC₉, 4.25 m 1H 6αH; 4.66,5.22 t,t 1/2H,1/2H protonat C₁₆ ; 4.97 q 1Hproton at C₁₁ ; 6.51 proton at C₁₃ ;

For the diastereoisomeric hydroxy ketones the mass spectrum shows thefollowing masses:

M⁺ 424 m/e and then M⁺ --H₂ O, M⁺ --HF, M⁺ --CH₃ OH/CH₂ O M⁺ --CH₂ ═CHOH(basis ion) M⁺ -115 M⁺ -44-59 and M⁺ --(CHF--CH₂ --C₆ H₁₁).

In mass spectrum of exo-diastereoisomer the following masses arepredominant: M⁺ --CH₃ OH and M⁺ -44-28; in that of endo-diastereoisomerthe predominant ones are M⁺ --CH₃ O and M⁺ -44-18.

From the 5-bromo derivative,13t-5-bromo-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester is prepared.

EXAMPLE 49

Substituting in the procedure of example 48 a phosphonate chosen from(2-oxo-4-cyclohexyl-butyl)-dimethylphosphonate and(2-oxo-4-phenyl-butyl)-dimethylphosphonate, the following were prepared:

13t-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester,13t-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoicacid methyl ester and their 6αH isomers.

EXAMPLE 50

To a suspension of 178 mg of NaH (75% mineral oil dispersion) inanhydrous tetrahydrofuran at 0° C. is added dropwise with stirring asolutionof 1.63 g of2-oxo-3-(m-chlorophenoxy)-propyl-dimethylphosphonate in 10 ml ofanhydrous THF. After 30 minutes of stirring, a solution of 1 g of5-(6'-exo-formyl-7'-endo-2'-oxa-bicyclo[3.3.0]octan-3' -yl)pentanoicacid methyl ester is added and stirring is continued for another hour.The mixture is acidified with aqueous NaH₂ PO₄, the organic phaseisseparated, and the aqueous phase is re-extracted with benzene. Fromthe combined organic extract, after chromatography on silica gel withCH₂Cl₂ :Et₂ O (95:5) as eluent, one obtains of 0.43 g of13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16-m-chlorophenoxy-17,18,19,20-tetranor-prost-13-enoicacid methyl ester (λ_(max) ^(MeOH) =227 mμ, ε=16,800) and 0.11 g ofthe6βH isomer (λ_(max) =224 mμ, ε=16,900). Both the diastereoisomersshow the mass peak m/e 436 in according to C₂₃ H₂₉ ClO₆. This ion isinvolved in the following fragmentation: M⁺ --H₂ O, M⁺ --OCH₃ /CH₃ OH,M⁺ -44, M⁺ --(O--C₆ H₄ Cl), M⁺ --H₂ O--(O--C₆ H₄ Cl) and M⁺ --(CH₂)₄--CO₂ CH₃, so furthermore confirming the proposed structure. Thefollowing differences are between the two diastereoisomers: the exo 6αll isomer shows a peak at M⁺ -32 and a little intense peak at M⁺ -44 onthe other hand the endo 6 βH isomer shows a peak at M⁺ -31 and anintense peak M⁺ -44.

EXAMPLE 51

The substitution of a phosphonate chosen from2-oxo-3-(m-trifluoromethylphenoxy)-propyl-dimethylphosphonate and2-oxo-3-(p-fluorophenoxy)-propyl-dimethylphosphonate in the procedure ofexample 50 leads to the following compounds, respectively:

13t-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16m-trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-enoicacid methyl ester,13t-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16-p-fluorophenoxy-17,18,19,20-tetranor-prost-13-enoicacid methyl ester, and their 6αHisomers.

The mass spectra of all the compounds agree with the proposed structureforexample showing the mass peak M⁺ -115; an interesting differencebetween the endo- and exo- trifluoromethyl analogous is that the masspeaks M⁺ --CH₃ OH and M⁺ --CF₃ --C₆ H₄ --OH are in the exo-isomer andthe mass peak M⁺ --CH₃ O and M⁺ --CF₃ --C₆ H₄ --O are in theendo-isomer.

EXAMPLE 52

The substitution of (2-oxo-3S-methyl-butyl)-dimethylphosphonate for thephosphonate in the procedure of example 48 gave13t-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16S-methyl-prost-13-enoic acidmethyl ester and its 6αH isomer. To a solution of 2.2 g of the 6βHisomer in 2.6 ml of pyridine, cooled to 0° C., is added 1.05 ml ofacetic anhydride. The solution is held at 0° C. overnight and then addedto an excess of cold 0.05 N sulfuric acid. Extraction with ethyl etherand evaporation to dryness give 2.3 g of13t-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-16S-methyl-prost-13-enoic acidmethyl ester-11-acetate (λ_(max) ^(MeOH) =229 mμ, ε=12,050).

875 mg of bromine in glacial acetic acid is added dropwise to a solutionofthe latter compound in 10 ml of glacial acetic acid, until a lightorange color appears. 1.52 g of anhydrous potassium carbonate is thenadded and the resulting mixture is held at 80° C. for 4-5 hours tocomplete the precipitation of potassium bromide. Excess acetic acid isremoved under vacuum, water is added, and the pH is brought to pH 6.8with alkaline hydrate. This is then extracted with ethyl ether and theorganic phase is reduced in volume.

Adsorption on silica gel and elution with methylene chloride:ethyl ether(70:30) gives 2.01 g of13t-6βH-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoicacid methyl ester-11-acetate, λ_(max) ^(MeOH) =249 mμ,ε=11,450.

The 6αH isomer is similarly prepared.

EXAMPLE 53

A solution of 2.06 g of (2-oxo-3S-methylheptyl)-dimethylphosphonate in20 ml of dimethoxyethane is added dropwise to a suspension of 0.265 g ofNaH (80% mineral oil dispersion) in DME (10 ml). After stirring for 30minutes, 1.6 g of N-bromosuccinimide is added and vigorous stirring iscontinued for 10 minutes. 1.35 g of5-(6'-oxo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester in 5 ml of dimethoxyethane is thenadded.The mixture is stirred for 1 hour and 20 ml of 30% NaH₂ PO₄ isadded. After the usual work-up, crude 14-bromo-enone is obtained.Separation on silica gel with methylene chloride:ethyl ether (85:15)gives0.9 g of13t-6βH-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoicacid methyl ester and 0.92 g of the 6αH isomer. Upontreatment with 0.4ml of pyridine and 0.2 ml of acetic anhydride, 0.2 g of the 6βH isomergives 0.205 g of the 11-acetoxy derivative, identical in all respectswith that made by the procedure of example 52.

EXAMPLE 54

A solution of 0.43 g of (2-oxo-octyl)-dimethylphosphonate in 10 ml ofbenzene is added dropwise to a suspension of 54 mg of NaH (80% mineraloildispersion) in 5 ml of benzene. After 1 hour, when the evolution ofH₂has ceased, 0.32 g of N-bromosuccinimide is added all at once. To thecarbanion thus prepared, of (1-bromo-2-oxo-octyl)-dimethylphosphonate isadded a solution of 270 mg of5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester in 8 ml of benzene. After 30 minutes,thereaction is quenched by the addition of 20 ml of a 10% solution ofNaH₂ PO₄. The organic phase, after being washed until neutral, gives0.31 g of 13t-6H-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acidmethyl ester; this is then separated into the 6αH and 6βH isomers.

EXAMPLE 55

Upon substitution of the (2-oxo-octyl)-dimethylphosphonate in theprocedureof example 54 with(2-oxo-4-cyclohexylbutyl)-dimethylphosphonate and(2-oxo-4-phenyl-butyl)-dimethylphosphonate, the following compounds wereprepared:13t-6βH-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester;13t-6βH-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoicacid methyl ester.

EXAMPLE 56

By substituting the formyl derivatives in examples 53, 54 and 55 with5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester,4-iodo-4-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester, and the corresponding 4-H derivative,thefollowing compounds were prepared:

13t-5-iodo-6βH-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoicacid methyl ester;

13t-4-iodo-5βH-5(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoicacid methyl ester;

13t-5βH-5(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoicacid methyl ester;

13t-5-iodo-6βH-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoicacid methyl ester;

13t-4-iodo-5βH-5(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoicacid methyl ester;

13t-5βH-5(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoicacid methyl ester;

13t-5-iodo-6βH-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester;

13t-5βH-5(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester;

13t-5-iodo-6βH-6(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoicacid methyl ester;

13t-5βH-5(9α)-oxide-11α-hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoicacid methyl ester.

EXAMPLE 57

A solution of 0.61 g of 2-oxo-octyl-triphenylphosphonium bromide in 6 mlofDMSO is added to a solution of 0.15 g of potassium t-butylate in 3 mlof DMSO while keeping the reaction temperature at 16°-19° C. 0.27 g of5-(6'-oxo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester in 8 ml of anhydrous tetrahydrofuran isthen added. After 30 minutes of stirring, an equal volume of water isadded and the mixture is extracted with ethyl ether. The combinedorganic extract is washed until neutral and the solvent is evaporated.Chromatography on silica gel (cyclohexane:ethyl ether, 40:60) gives 0.21gof 13t-6 H-6(9α)-oxide-11α-hydroxy-15-oxo-20-methyl-prost-13-enoicacidmethyl ester. Subsequent preparative thin layer chromatography (SiO₂-Et₂ O) allows separation of the 6αH and 6βH isomers.

EXAMPLE 58

A solution of d,l-13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-13-enoicacidmethyl ester (exo-isomer at greatest R_(f)), (0.9 g), in dry ethylether (30 ml) is dripped on to a stirred 0.1 M solution of Zn(BH₄)₂indry ethyl ether (30 ml), over 15 minutes. After 2 hours, the excessreagentis decomposed by cautious addition of saturated NaCl solution andaqueous 2N sulfuric acid. The organic layer is separated, washed toneutral and evaporated to dryness affording a residue which is adsorbedon silica gel,eluted with ethyl ether to yield 0.38 g of13t-6αH-6(9α)-oxide-11α,15R-dihydroxy-prostenoic acid methyl ester, asas oil, and 0.42 g ofd,l-13t-6αH-(9α)-oxide-11α,15S-dihydroxy-prostenoic acidmethyl ester,m.p. 69°-71° C. (mass spectrum m/e 350 M⁺ -18, 319 M⁺ -18-CH₃ O; 318M⁺ - 18--CH₃ OH). A solution in methanol (4 ml) of this ester is treatedwith 60 mg of lithiumhyroxide and water (0.8 ml) for 8 hours at roomtemperature. The methanol is removed in vacuum, the residue is dilutedwith water and extracted withethyl ether to remove neutral impurities.The alkaline phase is treated with aqueous saturated NaH₂ PO₄ solutionuntil to pH 5 and then extracted with ethyl ether. The later organicphases are collected to yield after evaporation of the solvents the freeacid d,l-13t-6αH-6(9α)-oxide-11α,15S-dihydroxy-prostenoic acid, m.p.105°-106° C. The 15R-hydroxy compound is a noncrystallizable oil.

In the same way using nat-keto compound in the reduction reaction withZn(BH₄)₂ we obtained besides the 15-epi alcohol, thenat-13t-6αH-6(9α)-oxide-11α,15S-dihydroxy-prostenoic acid methyl ester,m.p. 71°-72° C. [α]_(D) =+10.2°, [α]₃₆₅° =+32.2° (CHCl₃) and aftersaponification the free acid m.p. 101°-102° C. [α]_(D) =+6.34°, [α]₃₆₅°=+33.2° (CHCl₃).

Starting from the endo-diastereoisomers (more polar compounds), thefollowing esters were obtained:

13t-6βH-6(9α)-oxide-11α,15R-dihydroxy-prostenoic acid methyl ester (d,l,nat-, ent- oils);

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-prostenoic acid methyl ester (d,l,nat-, [α]_(D) =+24.5°, [α]₃₆₅° =+52.9° (CHCl₃) oil; ent- [α]_(D) =-22°,oil), and after saponification the followingfree acids:

13t-6βH-6(9α)-oxide-11α,15R-dihydroxy-prostenoic acid (d,l, nat-, ent-oils);

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-prostenoic acid (d,loil, nat-,m.p. 78°-80° C. [α]_(D) =+32.5°, [α]₃₆₅° =+11.6° (EtOH), ent- m.p.78°-79° C., [α]_(D) =-31° (EtOH)).

EXAMPLE 59

With the temperature of the reaction mixture kept at around -5° to -8°C., a solution of 159 mg of NaBH₄ in 7 ml propan-2-ol, is graduallyadded to a solution of 0.332 g of anhydrous CaCl₂ in propan-2-ol (7 ml);then, under stirring, a solution of 0.38 g of13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester in 3 ml of propan-2-ol is added to the above preparedCa(BH₄)₂ in a period of 40 minutes. The reaction mixture is kept understirring at a temperature ranging at ±5° C., then the excess reagent isdestroyed by addition of 5 ml of acetone and 2 ml of water. The solventisevaporated under vacuum and the residue is partitioned among water,0.1 N H₂ SO₄ and ethyl acetate. The organic extracts are collected,washed until neutral and after evaporation of solvent the residuechromatographed on silica gel (30 g) using CH₂ Cl₂ -ethyl ether 70:30 aseluent. The eluate yields 0.21 g of13t-6αH-6(9α)-oxide-11α,15R-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester, and 0.14 g of the 15S-epimer, m.p. 83°-84° C. (fromethyl ether). In the same way, reduction of the 6βH-isomer (220 mg)yields 0.1 g of13t-6βH-6(9α)-oxide-11α,15R-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid methyl ester, m.p. 63°-64° C. (from isopropylic ether), and 60 mgof 15S-alcohol.

EXAMPLE 60

A solution of 0.15 g of 13t-6αH-6(9α)-oxide-11α-hydroxy-15-keto-16-methyl-16-butoxy-18,19,20-trinor-prostenoicacid methyl ester in methanol (5 ml) is cooled at -5°+-10° C. andreduced by addition of a solution of NaBH₄ (30 mg) in water (0.5 ml).The reaction mixture is neutralized by addition of 15% aqueous NaH₂ PO₄solution after 15 minutes and then evaporated in vacuum. The aqueousresidue is extracted with ethylether to yield a crude mixture ofepimeric 15R,15S-alcohols. Chromatographic separation on silica gel (CH₂Cl₂ -ethyl ether 70:30 as eluent) affords respectively13t-6αH-6(9α)-oxide-11α,15R-dihydroxy 16methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester (45 mg)and 15S-hydroxy-epimer (62 mg).

EXAMPLE 61

By reduction of13t-5αH-5(9α)-oxide-11α-hydroxy-15-keto-16-methyl-16-butoxy-18,20-trinor-prostenoicacid methyl ester, under the same trial conditions as in the procedureof example 60 followed by chromatographic separation of the epimericalcohols (300 mg) on silica gel (12 g) with methylene chloride-ethylether 75:25 eluent, we respectively obtained 100 mg of13t-5αH-5(9α)-oxide-11α-15R-dihydroxy-16-butoxy-18,19,20-trinor-prostenoicacid methyl ester, and 110 mg of 15S-epimer. These are then saponifiedto yield the corresponding free acids.

EXAMPLE 62

Dropwise, to a stirred 0.12 M solution of zinchorohydride in ethyl ether(8ml) a solution of 0.135 g of13t-5-bromo-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-prostenoic acid methylester in 2 ml of anhydrous Et₂ O is added. The mixture is stirred for 2hours and the excess reagent is decomposed with water-2 NH₂ SO₄. Theorganic phase is separated, washed to neutral and evaporated to dryness.After TLC on silica gel with ethyl ether-ethyl acetate 90:10, 38 mg of13t-5-bromo-6αH-6(9α)-oxide-11α,15R-dihydroxy-prostenoicacid methylester and 46 mg of 15S-epimer were obtained.

EXAMPLE 63

Starting from13t-5,14-dibromo-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-prostenoic acidmethyl ester (0.2 g) and using a mixture of CH₂ Cl₂ -ethyl ether 60:40,during the chromatographic separation on silica gel, we obtained 0.056 gof 13t-5,14-dibromo-6βH-6-(9α)-oxide-11α,15R-dihydroxy-prostenoic acidmethyl ester and 0.098 g of 15-isomer. A solution of this product inmethanol is then hydrolized with aqueous LiOH to yield 72 mgof13t-5,14-dibromo-6αH-6(9α)-oxide-11α,15S-dihydroxy-prostenoic acid.

EXAMPLE 64

Using, in the procedure of example 60, isopropanol as solvent and MaBH₄(45 mg), the reduction of13t-6βH-6(9α)-oxide-11α-hydroxy-5-oxo-16-(m-trifluoromethyl)-phenoxy17,18,19,20-tetranor-prost-13-enoic acid methyl ester (0.47g) yields0.20 g of 13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoicacid methyl ester, [α]_(D) =+33.3° (MeOH) and 0.18 g of 15R-epimer. The6αH-15S-alcohol epimer is an oil with [α]_(D) =+12° (MeOH).

EXAMPLE 65

A solution in dry ethyl ether (20 ml) of13t-16S-methyl-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester (0.002 M, 0.72 ) is added to a stirred etheral solution ofzinc borohydride (0.01 M, 100 ml). The excess reagent is destroyed,after 30-45 minutes, by addition of 2N-sulphuric acid in NaCl saturatedaqueous solution. The organic phase is washed until neutral andevaporated to dryness. The residue is chromatographed on silica gel (25g)using methylene-chloride:ethyl ether (80:20) as eluent affording(7.5.10⁻⁴ M, 0.27 g) of the 15R-hydroxy-isomer and (1.1.10⁻⁴ M; 0.38 g)of the 15S-alcohol:13t-16S-methyl-6αH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoic acidmethyl ester. Using this procedure, the following methyl esters wereobtained:

13t-6βH-6(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-enoic acid;

13t-6βH-6(9α)-oxide-16R-methyl-11α,15S-dihydroxy-prost-13-enoic acid;

13t-6βH-6(9α)-oxide-16,16-dimethyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-6αH-6(9α)-oxide-20-methyl-11α,15S-dihydroxy-prost-13-enoic acid,m.p. 57°-59° C. [α]_(D) =+14°, [α]₃₆₅° =+47° (CHCl₃);

13t-6βH-6(9α)-oxide-20S-methyl-11α,15S-dihydroxy-prost-13-enoic acid,m.p. 38°-39° C., [α]_(D) =+21.7°, [α]₃₆₅° =+77° (CHCl₃);

13t-5-bromo-6βH-6(9α)-oxide-16S-methyl-11α,15S-dihydroxyprost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-16R-methyl-11α,15S-dihydroxyprost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-16,16-dimethyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-20-methyl-prost-13-enoicacid, [α]_(D) =+38°;

13t-5-iodo-6βH-6(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-16R-methyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-16,16-dimethyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-20-methyl-prost-13-enoicacid, [α]_(D) =+23°, [α]₃₆₅° =+78° (CHCl₃);

13t-5-chloro-6βH-6(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-5βH-5(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-enoic acid;

13t-5βH-5-(9α)-oxide-16,16-dimethyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-4-bromo-5βH-5(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-4-bromo-5βH-5(9α)-oxide-16R-methyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-4-bromo-5βH-5(9α)-oxide-16,16-dimethyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-4-iodo-5βH-5(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-4-chloro-5βH-5(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-16S-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-16R-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-20-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-15(S,R)-20-dimethyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-5βH-5(9α)-oxide-16S-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-5βH-5(9α)-oxide-16R-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-5βH-5(9α)-oxide-20-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-5βH-5(9α)-oxide-16(S,R)-20-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-16S-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-16R-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-20-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-16(S,R)-20-dimethyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-4-bromo-5βH-5(9α)-oxide-16S-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-4-bromo-5βH-5(9α)-oxide-16R-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-4-bromo-5βH-5(9α)-oxide-20-methyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

13t-4-bromo-5βH-5(9α)-oxide-16(S,R)-20-dimethyl-11α,15S-dihydroxy-14-bromo-prost-13-enoicacid;

together with their 15R-epimeric alcohols, when the corresponding15-keto compounds are submitted to reduction followed by chromatographicseparation. Starting from 6αH and 5αH diastereoisomeric 15-ketocompounds we prepare the corresponding 15S- and 15R-alcohols. All thesecompounds are then saponified to yield the corresponding free acids.

EXAMPLE 66

A solution of13t-5-iodo-6βH-6(9α)-oxide-16R-methyl-15-oxo-prost-13-enoic acid methylester (0.32 g) in ethyl ether (8 ml) is added to a stirred solution ofzinc borohydride in ethyl ether (25ml). After 30 minutes, the excessreagent was destroyed by addition of a saturated solution of NaCl and NH₂ SO₄. After the usual work up the organic phase is separated and thecrude residue is chromatographied on SiO₂ (eluent (CH₂ Cl₂ -ethyl ether)to yield 0.16 g of13t-5-iodo-6βH-6(9α)-oxide-16R-methyl-15R-hydroxy-prost-13-enoic acidmethyl ester and 0.095 g of 15R-epimer. Using this procedure thefollowing methyl esters were obtained:

13t-6βH-6(9α)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;

13t-6βH-6(9α)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;

13t-6βH-6(9α)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;

13t-5βH-5-(9α)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;

13t-5βH-5(9α)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;

13t-5βH-5(9α)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;

13t-5-bromo-6βH-6(9α)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;

13t-5-bromo-6βH-6(9α)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;

13t-5-bromo-6βH-6(9α)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-15S-hydroxy-20-methyl-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-15S-hydroxy-16S,20-dimethyl-prost-13-enoicacid;

together with their 15R-epimeric alcohols, when the corresponding15-keto compounds are submitted to reduction followed by chromatographicseparation.

Starting from 6αH and 5αH diastereoisomeric 15-keto compounds we preparethe corresponding 15S- and 15R-alcohols.

EXAMPLE 67

The following 15S-hydroxy-9α-oxide prostenoic acids methyl esterstogether with their 15R-epimeric alcohols are obtained after reductionof the corresponding 15-keto compounds using one of the proceduresdescribed in examples 58 to 66:

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-13-prostenoic acid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-13-prostenoic acid;

13t-4-chloro-6βH-6(9α)-oxide-11α,15S-dihydroxy-13-prostenoic acid;

13t-5,14-dibromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-13-prostenoic acid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoic acid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoicacid;

13t-5,14-dibromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoicacid;

13t-5-iodo-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoicacid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-13,19,20-trinor-prost-13-enoicacid;

13t-5,14-dibromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoicacid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihdyroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-5,14-dibromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-5-chloro-6βH-6(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-methyl-16-amyloxy-18,19,20-trinor-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-17-cycloheptyl-18,19,20-trinor-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18,19,20-tetrano-13-prostenoicacid;

13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-13-prostenoic acid;

13t-14-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-13-prostenoic acid;

13t-14-chloro-5βH-5(9α)-oxide-11α,15S-dihydroxy-13-prostenoic acid;

13t-4,14-dibromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-13-prostenoic acid;

13t-5βH-5-(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoic acid;

13t-14-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoicacid;

13t-4,14-dibromo-5βH-5(9α)-oxide-11α,15S-dibromo-20-methyl-13-prostenoicacid;

13t-4-iodo-5βH-5(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoicacid;

13t-4-iodo-14-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-20-methyl-13-prostenoicacid;

13t-14-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-4,14-dibromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-4-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-13-enoicacid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoicacid;

13t-14-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoicacid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-prost-13-enoicacid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-14-bromo-5βH-5(9α)-oxide-11α,15S-hydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-4,14-dibromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-4-iodo-5βH-5(9α)-oxide-11α,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-4-iodo-5βH-5(9α)-oxide-11α,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-4-iodo-5βH-5(9α)-oxide-11α,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid;

13t-4-iodo-5βH-5(9α)-oxide-11α,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoicacid.

In similar way, we prepare the diastereoisomeric αH-9α-oxide-15S- andαH-9α-oxide-15R-alcohols whenwe use αH-9α-oxide-15-keto diastereoisomeras starting material.

All these esters are then saponified to obtain the free acids.

EXAMPLE 8

0.46 g of13t-5βH-5(9α)-oxide-16S-methyl-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester are heated with pyridine (2 ml) and acetic anhydride (1ml). After 6 hours at room temperature the mixture is dilutedwith brine,acidified to pH 4.5-4.8 and extracted with ethyl ether. The combinedorganic phases are then evaporated to dryness yielding 0.48 g of11-acetoxy-derivative (λ_(max) ^(MeOH) =229 mμ, ε=11.058). A solution ofthis compound in ethyl ether is then added dropwise to a solution ofZn(BH₄)₂ in ethyl ether. After 30 minutes the excess reagent isdecomposed with a N solution of H₂ SO₄ and after the usual worke-up,0.47 g of13t-5βH-5(9α)-oxide-16S-methyl-11α,15(S,R)-dihydroxy-13-prostenoic acidmethyl ester 11-acetate are obtained. A solution of this mixture in CH₂Cl₂ (5 ml) cooled to about -5° C., -10° C., is treated with a solutionof BF₃ etherate (1.2×10⁻⁴ M) in CH₂ Cl₂ and then with a 5% solution ofdiazomethane in CH₂ Cl₂ until a persistent yellow coloration.Thereaction mixture is evaporated to half volume under vacuum, washed witha5% aqueous NaHCO₃ solution and water to neutral, and evaporated todryness to yield 0.47 g of13t-5βH-5(9α)-oxide-16S-methyl-11α-hydroxy-15(S,R)-methoxy-prost-13-enoicacid-11-acetate which is separated in the individual isomers bychromatography on SiO₂ using benzene-ethyl ether (85:15) as eluent. Onthe other hands, 0.21 g of the mixture of 15(S,R)-methoxy-derivatives isdissolved in dry methanol (4 ml) and selectively deacetilated bytreatment with 20 mg of K₂ CO₃ for 4hours at room temperature. Afterneutralization by dilution with aqueous NaH₂ PO₄, the methanolevaporated under vacuum and the residue is extracted with ethyl ether(2×5) ethyl acetate (2×6 ml). The combined organic phases are evaporatedto dryness to yield 180 mg of the crude13t-5βH-5(9α)-oxide-16S-methyl-11α-hydroxy-15(S,R)-methoxy-prostenoicacid methyl ester, which is then readily separated by means ofa silicagel column chromatography using CH₂ Cl₂ -ethyl ether 80:20 as eluent toyield the two pure isomers: 15S-methoxy and 15R-methoxy. Using the sameprocedure the following methyl esters were obtained:

13t-6βH-6(9α)-oxide-16S-methyl-11α-hydroxy-15S-methoxy-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-16R-methyl-11α-hydroxy-15S-methoxy-prost-13-enoicacid;

13t-6βH-6(9α)-oxide-20-methyl-11α-hydroxy-15S-methoxy-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-20-methyl-11α-hydroxy-15S-methoxy-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-11α-hydroxy-15S-methoxy-prost-13-enoic acid;

13t-5-bromo-6βH-6(9α)-oxide-16S-methyl-11α-hydroxy-15S-methoxy-prost-13-enoicacid,

and their epimeric 15R-methoxy compounds are obtained starting from thecorresponding 11-acetoxy-15-keto compounds. Using in this procedure theαH-diastereoisomer instead of the βH, the corresponding αH-15-methoxycompounds are also obtained. The same procedure can bealso utilized forany 15-keto compound, previously described and analogously an otherdiazo alkane can be used inside of diazomethane.

EXAMPLE 69

To a solution of 0.26 g of13t-6βH-6(9α)-oxide-15(S,R)-hydroxy-16S-methyl-prost-13-enoic acidmethyl ester in methylene chloride, treated with 0.3 ml of a solutionofBF₃ etherate in methylene chloride, cooled at -10÷-8° C., a solution ofdiazoethane in methylene chloride is added until a persistent yellowcoloration is formed. The solvent is evaporated under vacuum and theresidue chromatographed on silica gel using ethyl ether-methylenechloride 10:90 as eluent to yield 0.115 g of13t-6βH-6(9α)-oxide-15S-ethoxy-16S-methyl-prostenoic acid methylester,and 0.1 g of 15R-ethoxy isomer. When a mixture of 15S,15R-alcohols, forexample 13t-6βH-6(9α)-oxide-11α,15(S,R)-dihydroxy-16S-methyl-prostenoicacid, containing a free 11-hydroxy-group is submitted to the procedureof the examples 68 and 69, the simultaneous alkoxylation of the11-alcoholic function also occurs yielding with diazomethane for exampleafter chromatographic separation the13t-6βH-6(9α)-oxide-11α,15S-dimethoxy-16S-methyl-prostenoic acid methylester beside the 15R-epimeric derivative.

In a similar way the following 15S-alkoxy prostenoic derivatives wereobtained:

13t-5βH-5(9α)-oxide-11α,15S-dimethoxy-prostenoic acid;

13t-6βH-6(9α)-oxide-11α,15S-dimethoxy-prostenoic acid;

13t-6βH-6(9α)-oxide-5-bromo-11α,15-S-dimethoxy-prostenoic acid;

13t-6βH-6(9α)-oxide-5-iodo-11α,15S-dimethoxy-prostenoic acid;

13t-5βH-5(9α)-oxide-15S-methoxy-16S-methyl-prostenoic acid;

13t-6βH-6(9α)-oxide-15S-methoxy-16S-methyl-prostenoic acid;

13t-6βH-6(9α)-oxide-15S-methoxy-16R-methyl-prostenoic acid;

13t-6βH-6(9α)-oxide-15S-methoxy-16-methyl-16-butoxy-18,19,20-trinor-prostenoicacid; and their 15R epimers are obtained and when they are saponifiedwith LiOH in methanol the free acids are prepared. The same procedurecan be used to obtain diastereoisomeric αH-9α-oxide derivatives.

EXAMPLE 70

To a stirred solution of 1.33 g of13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acid methylester-11-acetate in 6 ml of toluene and 54 ml of benzene, cooled at +4°C., a solution of 1.67 g of methylmagnesium iodide inethyl ether isadded. After 20 minutes, the excess reagent is decomposed with an iced20% solution of ammonium chloride in water. After dilution with onevolume of ethyl ether the organic phase is washed with water, sodiumbicarbonate and water, dried over magnesium sulphate, treated with 0.1ml of pyridine and evaporated to dryness to yield 1.2 g of13t-6αH-6(9α)-oxide-11α,15(S,R)-dihydroxy-15-methyl-prostenoicacid-methylester-11-acetate, of which 0.2 g are separated into the purecomponent by thin layer chromatography on silica gel, with benzene-ether60:40 eluant. 1 g of the mixture of the two alcohols is dissolved inanhydrous methanol (20 ml) and stirred for 4 hours with 0.25 g of K₂CO₃. The mixture is evaporated to dryness, the residue is partitionedbetween ethyl ether and aqueous 15% NaH₂ PO₄. Theorganic phase isevaporated in vacuum and the residue is absorbed on silicagel (200 g).Elution with ethyl ether-isopropylic ether 80:20 affords 0.20 g of13t-6αH-6(9α)-oxide-11α,15R-dihydroxy-15-methyl-prost-13-enoic acidmethyl ester, and 0.36 g of 15S-epimer. 0.16 g of this compoundaredissolved in 12 ml of methanol and treated with 0.8 ml of water and 0.2gof K₂ CO₃. After 5 hours at room temperature the methanol is evaporatedunder vacuum, the residue is treated with 20% NaH₂ PO₄ and ethylacetate. The organic phase yields 0.14 g of13t-6αH-6(9α)-oxide-11α,15S-dihydroxy-15-methyl-prost-13-enoic acid. Thecorresponding 6βH-isomers are prepared in the same way.

EXAMPLE 71

To 1.79 g of 13t-5αH-5(9α)-oxide-11α-hydroxy-15-oxo-prost-13-enoic acidmethyl ester-11-acetate in 20 ml of anhydrous tetrahydrofurane, 50 mlof0.3 M ethynylmagnesium bromide in anhydrous tetrahydrofurane is added.Keep shaking for one hour, eliminate the excess reagent by treating withasaturated NH₄ Cl solution, concentrate the organic phase undervacuum,and take up with ethyl ether to yield 1.62 g of13t-5αH-5(9α)-oxide-11α,15(S,R)-dihydroxy-15-ethynyl-prost-13-enoic acidmethyl ester-11-acetate, which is dissolved in anhydrous methanol andtreated with 250 mg of anhydrous potassium carbonate for 3 hours undershaking. Evaporated under vacuum and dilute with 20% aqueous NaH₂ PO₄and ethyl ether. After evaporating the solvent, the organic phase yields1.41 g of13t-5αH-5(9α)-oxide-11α,15(S,R)-dihydroxy-15-ethynyl-prostanoic acidmethyl ester, which is separated into the two pure 15S-hydroxyand15R-hydroxy epimer by silica gel chromatography with benzene-ethyl ether1:1 as eluent, and after saponification of the 15S-hydroxyepimer with K₂CO₃ in methanol, there is yield of the13t-5αH-5(9α)-oxide-11α,15S-dihydroxy-15-ethynyl-prostenoic acid.

EXAMPLE 72

To a solution in tetrahydrofuran anhydrous (25 ml) of 1.41 g of13t-5-bromo-6βH-6(9α)-oxide-15-oxo-prost-13-enoic acid methyl ester, a0.5 M solution of magnesium vinyl bromide in tetrahydrofurane (25ml) isadded at 0°-5° C. and let stand for 4 hours at room temperature.Decompose the excess reagent with a saturated solution of ammoniumchloride, distil the tetrahydrofuran under vacuum and take up with ethylether. The organic phase is adsorbed on silica gel and eluted withmethylene chloride-ethyl ether to yield 0.41 g of13t-5-bromo-6βH-6(9α)-oxide-15R-hydroxy-15-vinyl-prostenoic acid methylester, and 0.62 g of 15S-isomer, which after saponification with LiOH inmethanol yields 0.49 g of pure13t-5-bromo-6βH-6(9α)-oxide-15S-hydroxy-15-vinyl-prostenoic acid.

EXAMPLE 73

A solution of 0.98 g of13t-5-bromo-6βH-6(9α)-oxide-11α-hydroxy-15-oxo-20-methyl-prostenoic acidmethyl ester-11-acetate in 30 ml of benzene-toluene (85:15)is cooled at3°-4° C. and to this a solution of 0.92 g of phenylmagnesium bromide inethyl ether-benzene 1:1 is added. Let stand for5 hours at roomtemperature, then decompose the excess reagent with an icedsolution of15% NH₄ Cl, wash the organic phase repeatedly with water to neutral thenevaporate. The crude 15-phenyl-15(S,R)-hydroxy derivative is dissolvedin anhydrous methanol to which is 0.25 g of K₂ CO₃ is added, keptshaking for 2 hours. Evaporate to dryness, dilute with aqueous 20% NaH₂PO₄ and ethyl ether, and from the organic phaseafter evaporation of thesolvent, there is a yield of 0.81 g of13t-5-bromo-6βH-6(9α)-oxide-11α,15(S,R)-dihydroxy-15-phenyl-20-methyl-prostenoicacid methyl ester, which after separation on silicagel with ethyl etherelution yields the individual 15S and 15R isomers.

EXAMPLE 74

By reaction of the corresponding 15-oxo-derivative with a reagentselected from the group of an halogenide of methylmagnesium, ethylmagnesium, vinylmagnesium, ethynyl magnesium and phenyl magnesium,working to one of the procedures given in example 70 to 73, thefollowing methylesters were prepared:

13t-6βH-6(9α)-oxide-15S-hydroxy-15-methyl-prostenoic acid;

13t-6βH-6(9α)-oxide-15S-hydroxy-15,20-dimethyl-prostenoic acid;

13t-6βH-6(9α)-oxide-15S-hydroxy-15-ethyl-prostenoic acid;

13t-6βH-6(9α)-oxide-15S-hydroxy-15-ethynyl-prostenoic acid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-methyl-prostenoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-ethyl-prostenoic acid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-vinyl-prostenoic acid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-ethynyl-prostenoic acid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-phenyl-prostenoicacid;

13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-15,20-dimethyl-prostenoic acid;

13-t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-methyl-prostenoicacid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-vinyl-prostenoic acid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-ethynyl-prostenoicacid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-ethyl-prostenoic acid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-15-phenyl-prostenoic acid;

13t-4-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-15-methyl-prostenoic acid;

13t-4-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-15,20-dimethyl-prostenoicacid;

13t-4-bromo-5βH-5(9α)-oxide-11α,15S-dihydroxy-15-ethynyl-prostenoicacid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-15-methyl-prostenoicacid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-15,20-dimethyl-prostenoic acid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-15-phenyl-prostenoicacid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-15-ethynyl-prostenoic acid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-15-vinyl-prostenoic acid;

13t-5βH-5(9α)-oxide-11α,15S-dihydroxy-15-methyl-prostenoicacid,

and their 15R-hydroxy epimers.

Analogously, starting from the αH-(9α)-oxide-15-keto-compounds weobtained the corresponding αH-(9α)-oxide-15-substituted alcohols.

EXAMPLE 75

To a solution of 0.5 g of13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-14-bromo-16S-methyl-prostenoicacid-methyl ester-11-acetate in 2 ml of dimethylformamide,dimethyl-t-butyl silane chloride (0.21 g) and triethylamine (0.16 g) areadded. Keep shaking for 2 hours, then dilute with 4 volumes of water andextract with ethyl ether. The organic phase, after the usual washings,evaporation of the solvent, and filtration through silica gel withcyclohexane-ethyl ether 90:10 eluent, yields 0.57 g of13t-6βH-6(9α)-oxide -11α,15S-dihydroxy-14-bromo-16S-methyl-prostenoicacid methyl ester-11-acetate-15-dimethyl-t.butylsilylether, from which,by transesterification in anhydrous methanol and 0.5 molar equivalentsof K₂ CO₃, the corresponding 11-hydroxy-derivative is yielded.

EXAMPLE 76

To 0.52 g of13t-5,14-dibromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prostenoic acidmethyl ester in 10 ml of dichloromethane, 2,3-dihydro-pyrane (0.27 g)and p-toluenesulphonic acid (4 mg) are added. Keep at room temperaturefor 3 hours, then wash with a 5% solution of KHCO₃ and water to neutral,and evaporate to dryness. Filter through silica gelwithcyclohexane-ethyl ether 90:10 as eluent, which yields 0.59 g of13t-5,14-dibromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prostenoic acidmethyl ester-11,15-bis-tetrahydropyranylether.

EXAMPLE 77

The 14-bromo-alcohols yielded by the foregoing examples, when treatedwith dimethyl-t.butylchlorosilane in dimethylformamide while, working tothe procedures as in example 75, or with an acetic ether such as2,3-dihydropyrane-1,4-diox-2-ene, 1-ethoxy-ethylene, and working to theprocedure of example 76, are then converted into the correspondingsilyloxy or the corresponding acetalic ethers.

EXAMPLE 78

Under an atmosphere of inert gas, to a stirred solution of 0.46 g of13t-14-bromo-6βH-6(9α)-oxide-15S-methoxy-16S-methyl-prost-13-enoic acidmethyl ester in anhydrous dimethylsulfoxide (5 ml), potassiumtert-butylate (0.15 g) is added and the stirring is continued for 30minutes. The reaction mixture is diluted with 2 volumes of water andstirred for 15 minutes, then extracted with ethyl ether. The organicphases are re-extracted with 2×5 ml of 0.2 N NaOH and then with wateruntil neutral and evaporated to dryness to give 30 mg of6βH-6(9α)-oxide-15S-methoxy-16S-methyl-prost-13-ynoic acid methyl ester.The combined aqueous phase are acidified to pH 5.1 and extracted withethyl ether. After evaporation of the solvent, 0.28 g of6βH-6(9α)-oxide-15S-methoxy-16S-methyl-prost-13-ynoic acid is obtained.

EXAMPLE 79

Under an atmosphere of inert gas, with stirring and rigorous exclusionof humidity, 0.84 g of trimethylsilylimidazole is added to an anhydrousdimethylsulfoxide solution of 0.445 g of13t-5αH-5(9α)-oxide-14-bromo-16R-methyl-prost-13-enoic acid. Stirring iscontinued for 30 minutes and then a solution of 0.19 g ofK-tert-butylate is added. After 30 minutes stirring, the mixture isdiluted with 3 volumes of water and stirred for 2 more hours. Afteracidification to pH 5.2, it is extracted with ethyl ether:hexane 80:20andthe organic extracts are dried and evaporated to dryness to give 0.31g of 5αH-5(9α)-oxide-16R-methyl-prost-13-ynoic acid.

EXAMPLE 80

To a solution of sodium methylsulfinylcarbanion, obtained by heating at60° C. for 3 hours and 30 minutes a suspension of 50 mg of 80% NaH in 8ml of anhydrous dimethylsulfoxide, a solution of13t-6βH-6(9α)-oxide-11α,15S-dimethoxy-14-bromo-16(S,R)-fluoro-20-methyl-prost-13-enoicacid methyl ester (0.86 g) in 5 ml of dimethyl sulfoxide is added withstirring under an atmosphere of inert gas, at a temperature of 18°-20°C. After 40 minutes of stirring an excess of 25% NaH₂ PO₄ is poured inand the mixture extracted with ethyl ether to give 0.51 g of6βH-6(9α)-oxide-11α,15S-dimethoxy-16(S,R)-fluoro-20-methyl-prost-13-ynoicacid methyl ester.

EXAMPLE 81

To a solution of 80 mg of sodium amide in 10 ml of dimethylsulfoxide asolution of13t-14-bromo-5αH-5(9α)-oxide-11α,15S-dihydroxy-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-enoicacid-11,15-bis-tetrahydropyranylether (0.65 g) in 5 ml ofdimethylsulfoxide is added. It is stirred for 2 hours and then dilutedwith water and extracted with ethyl ether. The ether extracts, afterreextraction with alkali are discarded. The aqueous alkaline extractsare acidified to pH 4.5 and extracted with ethyl ether to give 0.54 g of5αH-5(9α)-oxide-11α,15S-dihydroxy-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-ynoicacid-11,15-bis-tetrahydropyranyl ether. A solution of this compound(0.23 g) in anhydrous ethanol (5 ml) and 2,2-diethoxypropane (3 ml) istreated with 20 mg of p-toluenesulfonic acid. After 5 hours at roomtemperature it is neutralized with aqueous NaHCO₃, evaporated undervacuum and the residue partitioned between water and ethyl ether. Theorganic phase is evaporated and after passing the residue through silicagel 0.1 g of5αH-5(9α)-oxide-11α,15S-dihydroxy-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-ynoicacid ethyl ester is obtained. Deacetalization carried out on another 0.2g of product dissolved in 5 ml of acetone and treated with 3.5 ml of 0.2N oxalic acid for 8 hours at 40° C., after evaporation of the acetoneunder vacuum, extraction of the aqueous phase with ethyl ether andchromatography on silica gel with ethyl ether:ethyl acetate 95:5 thefree acid (95 mg) is obtained. In the same way, starting from13t-14-chloro-6αH-6(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoicacid-11,15-bis-dioxanylether the6αH-6(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-ynoicacid is obtained.

EXAMPLE 82

To a solution fo 0.48 g of13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-enoicacid methyl ester in 3 ml of anhydrous dimethylsulfoxide is added after30 minutes a solution of 1,5-diazabicyclo[5.4.0]undec-5-ene (0.25 g) in2 ml of anhydrous dimethylformamide and the reaction mixture maintainedfor 6 hours at 65° C. It is diluted with water acidified to pH 4.5,extracted withethyl ether. From the organic phase, after evaporation ofthe solvent and purification on silica gel (eluted with benzene-ethylether 80:20),6βH-6(9α)-oxide-11α,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-ynoicacid methyl ester (0.29 g) is obtained.

EXAMPLE 83

Using one of the procedures described in examples 78 to 82 and startingfrom the corresponding 13t-14-halo-prost-13-enoic acids, the followingprost-13-ynoic acids are prepared:

6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-ynoic acid;

6βH-6(9α)-oxide-11α,15R-dihydroxy-prost-13-ynoic acid;

6βH-6(9α)-oxide-15-methoxy-prost-13-ynoic acid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-16S-methyl-prost-13-ynoic acid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-16S,20-dimethyl-prost-13-ynoic acid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-16,16-difluoro-prost-13-ynoic acid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-20-methyl-prost-13-ynoicacid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-ynoicacid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-16-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-ynoicacid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-16-p-fluorophenoxy-17,18,19,20-tetranor-prost-13-ynoicacid;

6βH-6(9α)-oxide-11α,15S-dihydroxy-17-phenyl-18,19,20-trinor-prost-13-ynoicacid;

5βH-5(9α)-oxide-11α,15S-dihydroxy-16S-methyl-prost-13-ynoic acid;

5βH-5(9α)-oxide-11α,15S-dihydroxy-16S,20-dimethyl-prost-13-ynoic acid;

5βH-5(9α)-oxide-11α,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;

5βH-5(9α)-oxide-11α,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;

5βH-5(9α)-oxide-11α,15S-dihydroxy-prost-13-ynoic acid;

5βH-5(9α)-oxide-11α,15S-dihydroxy-20-methyl-prost-13-ynoicacid.

Starting from αH-(9α)-oxide compounds and using the same procedure, theepimeric αH-(9α)-oxide-13-ynoic compounds are prepared.

EXAMPLE 84

A solution of 0.35 g of mercuric acetate in methanol is added at roomtemperature, with stirring, to a solution of 0.54 g of5c,13t-9α,11α,15S-trihydroxy-prostadienoic acid methylester-11,15-bis-THP-ether (PGF₂α -bis-THP-ether-methyl ester). Afterstirring for 15 minutes, 50 mg of sodium borohydride is added in smallportions, the elemental mercury generated is removed by filtration andthe methanol is evaporated under vacuum. The residue is partitionedbetween dichloromethane/water; the organic phase, after washing withsodium bicarbonate and water until neutral, is evaporated to give 0.51 gof crude 13t-11α,15S-dihydroxy-6 H-6(9α)-oxide-prostenoic acidmethylester-11,15-bis-THP-ether. A solution of this in 10 ml of acetone addedto 8 ml of 0.2 N oxalic acid is heated to 40°-45° C. for 6 hours. Afterthe removal of the acetone under vacuum, the aqueous suspension isextracted with ethyl acetate (3×15 ml). The organic phase is washeduntil neutral and evaporated to dryness. The residue (approximately 0.45g) is adsorbed on silica gel (50 g) and eluted with ethyl ethercollecting fractions of 20 ml. From fractions 11 to 50,13t-11α,15S-dihydroxy-6αH-6(9α)-oxide-prostenoic acid methyl ester (0.11g; m.p. 67°-69° C.) is obtained. Then, after a mixture ofdiastereoisomers as 5-10% of ethyl acetate is added to ethyl ether,13t-11α,15S-dihydroxy-6βH-6(9α)-oxide-prostenoic acid methyl ester (0.16g; [α]_(D) =+19.62° (CHCl₃)) is collected. A sample of the latercompound, after crystallization, shows m.p. 40°-41° C., [α]_(D) =+25.2°,[α]₃₆₅° =+83.8° (CHCl₃). The crude free acidhas [α]_(D) =+18.3° (EtOH).

A sample is crystallized from pentane-ethyl ether affording purecrystalline 13t-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoic acid,m.p. 80°-81° C., [α]_(D) =+32.5°, [α]₃₆₅° =+111.6° (EtOH). Themassspectrum of the compound shows the following peaks (m/e, intensity,structure):

336 7% [M-H₂ O]⁺, 318 3% [M-2H₂ O]⁺ ; 292 100% [M-H₂ O-44]⁺ ; 264 30%[M-H₂ O-CH₂ CHCO₂ H]⁺; 235 4% [M-H₂ O-(CH₂)₄ CO₂ H].

The mass spectrum of the 6αH-diastereoisomer is substantially similar.

EXAMPLE 85

A solution of 0.19 g of 5c,13t-9α,11α,15S-trihydroxy-15-methyl-PGF₂α-methyl ester in 2.5 ml of THF is added to 0.3 g of mercuric acetate in1.5 ml water/3.0 ml THF. After 30 minutes of stirring, 60 mg of sodiumborohydride in 1.2 ml of water is added to the deep yellow suspension.After the mercury is separated, the THF is removed under vacuum and theaqueous suspension is extracted repeatedly with ethyl acetate. Theorganicphase, when washed until neutral and evaporated to dryness,yields 0.16 g of product which is purified by thin layer chromatographyto give 0.04 g of13t-11α,15S-dihydroxy-6αH-6(9α)-oxide-15-methyl-PGF.sub.2α -methylester, [α]_(D) =+6.2° (CHCl₃) and 0.034 g of the 6βH-6(9α)-oxide-isomer,[α]_(D) =+19.62° (CHCl₃).

EXAMPLE 86

0.43 g of 5c,13t-9α,15S-dihydroxy-16R-methyl-prostadienoic acid methylester-15-dioxanyl ether in methanol (2.5 ml) is reacted with a solutionof 0.38 g of mercuric bromide in methanol. The reaction mixture is heldat room temperature for 15 minutes and overnight at 0° C. Thecrystalline precipitate which forms is isolated by filtration to give0.36 g of 13t-15α-hydroxy-16R-methyl-6 H-6(9α)-oxide-5-bromomercuricprostenoic acid methyl ester, from which the mercury is removed upontreatment with sodium borohydride to give 0.12 g of13t-15S-hydroxy-16R-methyl-6 H-6(9α)-oxide-prostenoicacid methyl ester.Column chromatography on silica gel affects the separation into the6αH-6(9α)-oxide and 6βH-6(9α)-oxide diastereoisomers.

EXAMPLE 87

A solution of 0.55 g of 5c-9α,11α,15S-trihydroxy-prostenoic acid methylester in 2.5 ml of DME is added to a solution of 0.5 g of mercuricacetate in 2 ml of water/4 ml of DME. After 15 minutes, the reactionmixture is treated with a solution of 0.08 g of sodium borohydride in1.2 ml of water, the mercury is separated, the DME is removed undervacuum, and the residue is extracted several times with dichloromethane.The organic phase is evaporated to dryness, adsorbed on silica gel andeluted with ethyl ether/ethyl acetate to give 0.21 g of11α,15S-dihydroxy-6αH-6(9α)-oxide-prostenoic acid methylester and 0.18 gof the 6βH-6(9α)-oxide isomer.

EXAMPLE 88

A solution of 116 mg of5c-9α,11α,15S-trihydroxy-17-cyclohexyl-20,19,18-trinor-prost-5-en-13-ynoicacid methyl ester-11,15-bis-THP-ether in 1.5 ml of methanol istreatedwith 64 mg of mercuric acetate in 1.5 ml of methanol. After 10 minutes,25 mg of sodium borohydride is added. Methanol is removed under vacuum,the mercury is separated and the product is dissolved in water/ethylacetate. Evaporation of the organic phase to dryness affords crude11α,15S-dihydroxy-6H-6(9α)-oxide-17-cyclohexyl-20,19,18-trinor-prost-13-ynoic acid methylester-11,15-bis-THP-ether (100 mg); this is treated in acetone (4 ml)with 2.5 ml of 0.2 N oxalic acid overnight at 40° C. After removal ofthe acetone under vacuum, the mixture is extracted with ethyl acetate.Evaporation of solvent gives a residue which is purified on silica gel(eluent, ethyl ether) to give 28 mg of11α,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-6αH-6(9α)-oxide-prost-13-ynoic acid methyl ester, [α]_(D) =+17.2°, [α]₃₆₅° =+54°, and 12.5 mgof the 6βH-6(9α)-oxide-isomer, [α]_(D) =+26.5°, [α]₃₆₅° =+84° (EtOH); M⁺406, M-H₂ O⁺ 388. Under the same conditions,5c-9α,11α,15S-trihydroxy-15S-methyl-prost-5-en-13-ynoic acid methylester-11,15-bis-THP-ether gives11α,15S-dihydroxy-16S-methyl-6αH-6(9α)-oxide-prost-13-ynoic acid methylester and its 6βH-6(9α)-oxide isomer.

EXAMPLE 89

0.24 g of13t-11α,15S-dihydroxy-6αH,6(9α)-oxide-16-methyl-16-butoxy-20,19,18-trinor-prostenoicacid methyl ester and 0.13 g of the 6βH-6(9α)-oxide isomer are obtainedfrom the reaction of 1.01 molar equivalent of mercuric acetate (636 mg)in 10 ml of methanol and 1.1g of5c,13t-9α,11α,15S-trihydroxy-16-methyl-16-butoxy-20,19,18-trinor-prostadienoicacid methyl ester-11,15-bis-THP-ether in 5 ml of methanol.The mercurycompound so prepared is reduced in situ by the cautious addition of 85mg of sodium borohydride in small portions. The methanolic solution isthen decanted from the solid residue and reduced in volume. 10ml of 0.2N aqueous oxalic acid and 20 ml of acetone are added, and the resultingmixture is held at 50° C. for 12 hours. The organic solvents are removedunder vacuum, and the resulting solution is saturatedwith sodium sulfateand extracted with ethyl acetate. The organic phase is washed with 30%ammonium sulfate (2×5 ml) and 2.5 ml of water; afterdrying over NaSO₄,it is evaporated to give a crude residue which is purified on silica gelusing an eluent containing an increasing fraction of benzene-methylacetate, to give the isomeric 6αH-6(9α)-oxide and 6βH-6(9α)-oxide. Fromthe abovereaction with 16-m-chloro-phenoxy,16-p-fluoro-phenoxy, and16-m-trifluoromethyl-phenoxy-5c,13t-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-prost-5,13-dienoicacid methyl ester-11,15-bis-THP-ether and the analogous17-phenyl-18,19,20-trinor-derivative were obtained respectively:

13t-11α,15S-dihydroxy-6βH-6(9α)-oxide-17-phenyl-20,19,18,-trinor-prostenoicacid methyl ester, [α]_(D) =+28°;

13t-11α,15S-dihydroxy-6βH-6(9α)-oxide-16-m-chloro-phenoxy-20,19,18,17-tetranor-prostenoicacid methyl ester, [α]_(D) =+31°;

13t-11α,15S-dihydroxy-6βH-5(9α)-oxide-16-p-fluoro-phenoxy-20,19,18,17-tetranor-prostenoicacid methyl ester, [+]_(D) =+30° C.;

13t-11α,15S-dihydroxy-6βH-6(9α)-oxide-16-m-trifluoromethylphenoxy-20,19,18,17-tetranor-prostenoicacid methyl ester, [α]_(D) =+33°;

and their 6αH-6(9α)-oxide isomers which show [α]_(D) ranging between +8°and 12° in CHCl₃.

EXAMPLE 90

Using the16S-fluoro-17-cyclohexyl-5c,13t-9α,11α,15S-trihydroxy-20,19,18-trinor-prosta-5,13-dienoicacid methyl ester-11,15-bis-THP-ether, in the procedure of example 89,the 13t-11α,15S-dihydroxy-6βH-6(9α)-oxide16S-fluoro-17-cyclohexyl-20,19,18-trinor-prost-13-enoic acid-methylester and its (6βH-6(9α)-oxide diastereoisomer are obtained.

EXAMPLE 91

0.12 g of 13t-11α,15S-dihydroxy-6βH-6(9α)-oxide-prost-13-enoicacidmethyl ester in 6 ml of methanol is reacted with a 0.5 N aqueoussolution of lithium hydrate (2 ml). After six hours, the methanol isremoved under vacuum. The residue is diluted with water (2 ml) andextracted with ethyl ether to remove neutral impurities. The alkalineaqueous phase is acidified by treatment with 4 ml of 30% aqueous NaH₂PO₄ and extracted several times with ethyl ether. The later combinedether extracts are washed with water (2×1 ml) and dried; removal of thesolvent affords 91 mg of13t-11α,15S-dihydroxy-6βH-6(9α)-oxide-prost-13-enoic acid, m.p. 78°-80°C., [α]_(D) =+31° (EtOH). This procedure is used for saponification ofthe esters from the precedingexamples to the corresponding free acids.

EXAMPLE 92

11α,15S-dihydroxy-6βH-6(9α)-oxide-16S-methyl-prost-13-ynoic acid (0.11g) in methylene chloride is treated with 1.5 molar equivalent ofdiazomethane in methylene chloride. After 15 minutes, solvent is removedunder vacuum and the residue adsorbed on silica gel. Elution with ethylether/benzene (70:30) gives, in the following order, 12 mg of11α-hydroxy-15S-methoxy-6βH-6(9α)-oxide-16S-methyl-prost-13-ynoic acidmethyl ester and 78 mg of11α,15S-dihydroxy-6βH-6(9α)-oxide-16S-methyl-prost-13-ynoic acid methylester.

Using in this procedure diazoethane in side of the diazomethane,11α-hydroxy-15S-ethoxy-6βH-6(9α)-oxide-16S-methyl-prost-13-ynoic acidethyl ester is obtained.

EXAMPLE 93

A solution of l₂ (0.33 g) in methylene chloride is added to a suspensionof finely divided calcium carbonate in 6 ml of methylene chloridecontaining 0.54 g of 5c,13t-9α,11α,15S-trihydroxy-prostadienoic acidmethyl ester-11,15-bis-tetrahydropyranyl ether (PGF₂α-bis-tetrahydropyranyl ether methyl ester). The reaction mixture iscooledin an ice/water bath and kept in darkness. After three hours ofstirring, inorganic compounds are removed by filtration and the organicphase is washed with 0.25 N sodium thiosulfate and water. Removal of thesolvent affords 0.66 g of crude 13t-5-iodo-6H-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoic acid methylester-11,15-bis-tetrahydropyranyl ether. A solution of this in 10 ml ofacetone is added to 8 ml of 0.1 N oxalic acid and heated to 45°-46° C.for 4 hours. The acetone is then removed at reduced pressure and theaqueous suspension is extracted with ethyl acetate (3×12 ml); theorganic phase is washed until neutral and evaporated to dryness. Theresidue (0.42 g) is separated on silica gel with ethyl ether eluent.Elution of the high R_(f) fraction with acetonegives 0.14 g of13t-5-iodo-6αH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoic acid methylester, while the low R_(f) portion is 0.20 g of13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoic acid methylester. The methyl ester of the following acids were preparedanalogously:

13t-16S-methyl-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoicacid;

13t-20-methyl-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoicacid, [α]_(D) =+23°, [α]₃₆₅° =+78° (CHCl₃);

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoicacid;

13t-5-iodo-6αH-6(9α)-oxide-11α,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-13-enoicacid;

13t-5-iodo-6αH-6(9α)-oxide-11α,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-13-enoicacid;

13t-5-iodo-6βH-6(9α)-oxide-15S-hydroxy-prost-13-enoic acid;

13t-5-iodo-6αH-6(9α)-oxide-15S-hydroxy-prost-13-enoic acid;

13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-ynoic acid;

13t-5-iodo-6αH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-ynoic acid;

5-iodo-6βH-6(9α)-oxide-16S-methyl-11α,15S-dihydroxy-prost-13-ynoic acid;

5-iodo-6βH-6(9α)-oxide-20-methyl-11α,15S-dihydroxy-prost-13-ynoic acid,[α]_(D) =+20° (CHCl₃).

EXAMPLE 94

To a solution of 0.22 g of 5c,13t-9α,11α,15S-trihydroxy-15-methyl-PGF₂α-methyl ester in 10 ml of CH₂ Cl₂ and 0.1 ml of pyridine is addeddropwise a solution of 180 mg of iodine in methylene chloride. Theresulting mixture is stirred for 1 hour. After dilution with water andwashing of the organic phase with 0.1 N sodium thiosulfate and wateruntilneutral, the solution is evaporated in vacuum to a small volume andadsorbed on a silica gel plate 0.5 mm in thickness. After developmentwithethyl ether and elution with acetone, 0.052 g of13t-15-methyl-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoicacid methyl ester and 0.021 g of the isomeric 5-iodo-6αH-6(9α)-oxide areobtained.

EXAMPLE 95

0.288 g of 5c-16,16-dimethyl-9α,11α,15S-trihydroxy-prost-5-enoic acidmethyl ester in a solution of 60 mg of pyridine in methylene chloride (8ml) is reacted with 115 ml of bromine in methylene chloride. After 30minutes, starting material has completely disappeared; the organic phaseis washed with water, then 5% aqueous metabisulfite, and then wateruntil neutral to give, after removal of the solvent and purification byTLC on silica gel with ethyl ether as eluent, 0.083 g of16,16-dimethyl-5-bromo-6βH-6(9α)-oxide-prostanoic acid methyl ester and0.04 g of 6αH-diastereoisomer.

The following compounds were prepared analogously:

13t-16,16-dimethyl-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoicacid;

13t-16,16-dimethyl-5-bromo-6αH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoicacid.

EXAMPLE 96

To a solution of hydrotribromide pyrrolidone (1.1 molar equivalents) inanhydrous tetrahydrofuran (6 ml) is added a solution of5c,13t-9α,11α,15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5,13-dienoicacid methyl ester-11,15-bis-tetrahydropyranyl ether (0.7 g)in 6 ml oftetrahydrofuran. The mixture is stirred for 12 hours, the precipitatewhich forms is removed by filtration, and the tetrahydrofuran solutionis diluted with 2 volumes of acetone and treated with 4 g of potassiumiodide. After 4 hours at room temperature, the iodine liberated isdecomposed with sodium matabisulfate, 1.5 volumes of 0.1 N aqueousoxalic acid is then added and the mixture heated to 48° C. for 4 hours.The mixture is reduced under vacuum and extracted with ethyl acetate.Separation on TLC gives 0.14 g of13t-5-bromo-6αH-6(9α)-oxide-11α,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoicacid methyl ester and 0.11 g of the 5-bromo-6βH- 6(9α)-oxide. Using theprocedures of the examples 95 and 96, the following 6(9α)-oxides wereobtained:

5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-ynoicacid methyl ester;

5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prostanoic acid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoic acid;

13t-20-methyl-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoicacid;

13t-15-methyl-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-prost-13enoicacid;

13t-15-methyl-15-bromo-6αH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoicacid;

13t-16S-methyl-5-bromo-6αH-6(9α)-oxide-11α,15S-dihydroxy-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoicacid;

13t-5-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-17,18,19,20-tetranor-16m-trifluoromethyl-phenoxy-prost-13-enoicacid.

EXAMPLE 97

A solution of 0.1×10⁻³ M of a methyl ester, prepared according toexamples 93 to 96 in 2 ml of methanol is treated with 1 ml of an aqueoussolution of lithium hydrate (0.2×10⁻³ moles). The mixture is stirred for3 hours, evaporated nearly to dryness, diluted with5 ml of water, andextracted with ethyl ether.

The organic phase is washed with 0.1 N LiOH (2 N) and water, and is thendiscarded. The aqueous phase is acidified to pH 4.8 with 30% aqueousNaH₂ PO₄ and extracted with ethyl ether to give the free acid.

We claim:
 1. A compound selected from the group consistingof:13t-6βH-6(9α)-oxide-15S-methoxy-16-methyl-16-butoxy-18,19,20-trinor-prostenoicacid, and the corresponding methyl ester, the 15R-epimer and the6αH-diastereoisomers thereof;13t-6αH-6(9α)-oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester and the corresponding free acid, as well as the6βH-diastereoisomers thereof and the 5-chloro, 5-bromo and 5-iododerivatives thereof; 13t-6H-6(9α)-oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester and the corresponding free acid;13t-6αH-6(9α)-oxide-11α,15R-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prostenoicacid methyl ester and the corresponding free acid, the15S-hydroxy-epimer and the 6βH-diastereosomers thereof;13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoicacid methyl ester and the corresponding free acid;13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prost-13-enoicacid methyl ester and the corresponding free acid;13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-methyl-16-amyloxy-18,19,20-trinor-prost-13-enoicacid methyl ester and the corresponding free acid.and thepharmaceutically or veterinarily acceptable salts of the above mentionedacids.
 2. A compound of formula (I) ##STR54## where q is 1;R is a freeor esterified carboxy group, wherein the esterified carboxy group is ofthe formula --COOR_(c), wherein R_(c) is a C₁ -C₁₂ alkyl group, or a C₂-C₁₂ alkenyl group; Z₁ is hydrogen or halogen; p is zero or an integerof 1 to 7; R₁ is hydrogen, hydroxy, C₁ -C₆ alkoxy, benzyloxy, C₂ -C₁₂alkanoyloxy, and benzoyloxy; Y is chosen from the group of 13 CH₂ --CH₂--, ##STR55## wherein Z₂ is hydrogen or halogen, or --C.tbd.C--; one ofR₂ and R₅ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl C₂ -C₆ alkynyl,phenyl, α-naphthyl, or β-naphthyl, and the other is hydroxy, C₁ -C₆alkoxy, benzyloxy or R₂ and R₅, taken together, form an oxo group; eachof R₃ and R₄, which are the same or different, may be hydrogen, C₁ -C₆alkyl or fluorine or R₃ and R₄, taken together with the carbon atomwhich they are linked, form the radical ##STR56## each of n₁ and n₂,which are the same or different, is zero or an integer of 1 to 6; X is--O-- or --S--; R₆ is (a) hydrogen, (b) C₁ -C₄ alkyl, or C₃ -C₉ (c)cycloalkyl or C₃ -C₉ cycloalkenyl, unsubstituted or substituted by oneor more substituents selected from the group consisting of C₁ -C₆ alkyland C₁ -C₆ alkoxy, and the pharmaceutically and veterinarily acceptablesalts thereof.
 3. A compound according to claim 2, wherein Y is##STR57##
 4. A compound according to claim 2, wherein y is --C.tbd.C--.5. A compound according to claim 3 or 4 whereinR is carboxy ormethoxy-carbonyl; Z₁ is hydrogen; R₁ is hydrogen or hydroxy; one of R₂and R₅ is hydrogen or C₁ -C₆ alkyl and the other is hydroxy; one of R₃and R₄ is hydrogen or methyl and the other hydrogen, methyl or fluorine;X is --O--; n₁ is zero and n₂ is zero, 1 or 2; R₆ is C₁ -C₄ alkyl or C₅-C₇ cycloalkyl, and the pharmaceutically and veterinarily acceptablesalts thereof.
 6. A compound according to claim 5 wherein R₁ is hydroxy;one of R₂ and R₅ is hydrogen or C₁ -C₂ alkyl and the other is hydroxy;and R₆ is cyclohexyl, and the pharmaceutically and veterinarilyacceptable salts thereof. 7.13t-6βH-6(9α)-oxide-11.alpha.,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoicacid methyl ester, and the corresponding free acid and pharmaceuticallyor veterinarily acceptable salts thereof. 8.13t-14-bromo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-enoicacid methyl ester, and the corresponding free acid and pharmaceuticallyor veterinarily acceptable salts thereof. 9.6βH-6(9α)-oxide-11α,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-ynoicacid methyl ester, and the corresponding free acid and pharmaceuticallyor veterinarily acceptable salts thereof. 10.13t-5-iodo-6βH-6(9α)-oxide-11α,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoicacid methyl ester as well as the 15R-hydroxy epimers, all theαH-diastereomers and free acids corresponding to said ester, and thepharmaceutically or veterinarily acceptable salts of said acids.
 11. Apharmaceutical or veterinary composition, suitable for use as ahypotensive agent, said composition comprising a therapeuticallyeffective amount of a compound as claimed in claim 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 and a pharmaceutically and/or veterinarily acceptable carrierand/or diluent.
 12. A pharmaceutical or veterinary composition, suitablefor use as a vasodilatory agent, said composition comprising atherapeutically effective amount of a compound as claimed in claim 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 and a pharmaceutically and/or veterinarilyacceptable carrier and/or diluent.
 13. A pharmaceutical or veterinarycomposition, suitable for use as an anti-aggregating agent, saidcomposition comprising a therapeutically effective amount of a compoundas claimed in claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and apharmaceutically and/or veterinarily acceptable carrier and/or diluent.14. A pharmaceutical or veterinary composition, sutiable for use as ananti-thrombotic agent, said composition comprising a therapeuticallyeffective amount of a compound as claimed in claim 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 and a pharmaceutically and/or veterinarily acceptable carrierand/or diluent.
 15. A pharmaceutical or veterinary composition, suitablefor use as a luteolytic agent, said composition comprising atherapeutically effective amount of a compound as claimed in claim 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 and a pharmaceutically and/or veterinarilyacceptable carrier and/or diluent.
 16. A pharmaceutical or veterinarycomposition, suitable for use as a cytoprotective agent active on themucous membranes of the gastrointestinal tract, said compositioncomprising a therapeutically effective amount of a compound as claimedin claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and a pharmaceutically and/orveterinarily acceptable carrier and/or diluent.
 17. A pharmaceutical orveterinary composition, suitable for use as an anti-secretory agent,said composition comprising a therapeutically effective amount of acompound as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and apharmaceutically and/or veterinarily acceptable carrier and/or diluent.18. A pharmaceutical or veterinary composition, suitable for use as abronchodilatory agent, said composition comprising a therapeuticallyeffective amount of a compound as calimed in claim 1, 2, 3, 4, 5, 6, 7,8, 9 or 10, and a pharmaceutically and/or veterinarily acceptablecarrier and/or diluent.
 19. A pharmaceutical or veterinary composition,suitable for use as an anti-asthmatic agent, said composition comprisinga therapeutically effective amount of a compound as claimed in claim 1,2, 3, 4, 5, 6, 7, 8, 9 or 10, and a pharmaceutically and/or veterinarilyacceptable carrier and/or diluent.
 20. A pharmaceutical or veterinarycomposition, suitable for use as an uterus stimulant, said compositioncomprising a therapeutically effective amount of a compound as claimedin claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and a pharmaceutically and/orveterinarily acceptable carrier and/or diluent.